Matrix carrier compositions, methods and uses

ABSTRACT

Provided is a matrix carrier composition for use in pharmaceutical delivery system, the composition comprising an intermolecular association of at least a first solid phase comprising nanoparticles having hydrophobic surface, wherein the size of the nanoparticles is in the range of about 5-1000 nm, a second solid phase, comprising a biopolymer having hydrophilic and hydrophobic parts, and a continuous phase comprising oil associated with the first and said second solid phases.

RELATED APPLICATION DATA

This application is a continuation of U.S. patent application Ser. No.13/381,225, filed Dec. 28, 2011 (published as US 20120100216), which isthe U.S. National Stage of International Application No.PCT/IL2010/000551, filed Jul. 8, 2010, which claims the benefit of U.S.Provisional Patent Application No. 61/224,100, filed Jul. 9, 2009, thecontents of each of which are expressly incorporated by reference intheir entireties for all purposes.

FIELD OF THE INVENTION

The present invention relates to matrix carrier compositions, methodsfor their preparations and uses thereof, for example, in pharmaceuticaldelivery systems.

BACKGROUND

Oral delivery is considered to be a convenient and widely accepted routeof drug administration. Achieving good oral bioavailability for drugs isa cornerstone for an effective oral therapy. The use of an effectivecarrier for drugs having low bioavailability enables an effective oraladministration with improve drug potency and may be used for new drugs,as well as for old medicines that have not historically been availableorally.

The term bioavailability with respect to oral administration of drugs isdirected to the fraction of drug that has reached the systemiccirculation after oral administration, while taking into account bothabsorption and metabolism of the drug. The bioavailability may beaffected/dependent on several factors, some of which are related to theGastrointestinal (GI) tract and some are related to the metabolism ofthe drug before entering the systemic circulation. The factors include,for example, such factors as: GI motility, GI pH and enzymaticcomposition including protease, lipase, nuclease, and the like, Particle(active drug) size, physicochemical interaction with gut content,metabolism of the drug by enzymes and electrolytes in the GI tract,metabolism during the first pass clearance of the drug (such as, forexample, metabolism of the drug in the liver), Chemical characteristicof the drug (such as, for example, low lipid solubility, acidity of thedrug), and the like.

With respect to protein drugs, two main factors limit their use by oralroute of administration. One is the rapid degradation of the proteindrugs, which occurs in GI tract by intestinal enzymes and in mucosaltissues that generally cover the body cavities. The other factor thatlimits the oral administration of protein drugs is that most proteindrugs are relatively large molecules and therefore do not easily crossesthe intestinal epithelium. As a result, the bioavailability of orallyadministered protein-based drugs is typically extremely low.Accordingly, the most common route of protein drugs administration isthe parenteral route, which has several drawbacks, such as, for example,being inconvenient to the patients, and being more expensive in terms ofdrug administration. There is therefore an unmet medical need for aneffective non-parenteral mode of administration of protein drugs thatwill provide protection against biological degradation, improvepharmacokinetics and reduce toxicity. Although sophisticatednon-parenteral pharmaceutical systems, such as intra-nasal or inhaledsystems, have been developed, oral administration is more favorable,having the major advantage of convenience for increased patientcompliance. Various strategies for oral administration of protein drugshave been suggested, such as for example in the following publications:U.S. Pat. No. 7,090,868, U.S. Pat. No. 7,195,780, U.S. Pat. No.7,316,818, WO 06/062544, U.S. Pat. No. 6,071,535, U.S. Pat. No.5,874,105, U.S. Pat. No. 6,551,576, U.S. Pat. No. 6,808,720, U.S. Pat.No. 7,083,572, US 2007/0184076, WO 06/097793, WO 05/094785, WO 03/066859and EP0491114B1.

Additionally, since bioavailability may be low for non-protein drugsthere is also a growing need for the development of a drug deliverysystem that can protect the drug from the environment and may direct thedrug to a targeted site or organ, obviating unwanted side effects whilesimultaneously reducing dose and toxicity, improve potency of the drug,and improve the drug's bioavailability.

SUMMARY

The following embodiments and aspects thereof are described andillustrated in conjunction with systems, tools and methods which aremeant to be exemplary and illustrative, not limiting in scope.

According to some embodiments there is provided a matrix carriercomposition for use in a pharmaceutical composition with apharmaceutical agent. The matrix comprises an intermolecular associationof at least a first solid phase, preferably nanoparticles with size inrange 5-1000 nm having hydrophobic surface; a second solid phase,preferably a biopolymer (such as, for example, a polysaccharide) havingboth hydrophilic and hydrophobic parts; and a continuous phase of oilassociated with all the ingredients of the matrix.

There are further provided methods for manufacturing matrix carriercompositions and methods for the use of matrix carrier compositions.

According to some embodiments, there are provided matrix carriercompositions, suitable for the delivery of a pharmaceutical agent,comprising a particulate matter comprising pharmacologically inertnanoparticles, in non-covalent association with a biopolymer and apharmaceutical agent, wherein the particulate matter is associated witha continuous phase of oil. According to additional embodiments, thereare further provided methods of manufacturing matrix carriercomposition, pharmaceutical compositions comprising the same, andtherapeutic methods utilizing same. In some embodiments, the delivery isoral delivery. In some embodiments, the delivery is parenteral. In someembodiments, the delivery is topical.

According to some embodiments, there is provided pharmaceuticalcomposition, including an oil comprising particulate matter, wherein theparticulate matter comprises a biopolymer in non-covalent associationwith silica nanoparticles having a hydrophobic surface; and apharmaceutical agent, non-covalently associated with the silicananoparticles and the biopolymer. According to some embodiments, thereis provided a method of manufacturing a pharmaceutical composition, themethod includes: mixing nanoparticles with a biopolymer, whereby thenanoparticles form a non-covalent association with the biopolymer;mixing a pharmaceutical agent with oil, and mixing the nanoparticles andbiopolymer with the oil, wherein the pharmaceutical agent forms anon-covalent association with the nanoparticles and the biopolymer andwherein the inert nanoparticles, the biopolymer, and the pharmaceuticalagent are associated with the oil.

According to further embodiments, the pharmaceutical composition isanhydrous.

According to further embodiments, the matrix carrier composition ispreferably in the absence of water.

According to further embodiments, the matrix carrier composition ispreferably in the absence of additional surfactants.

In some embodiments the inert nanoparticles include silicananoparticles, where at least 80% of silica is hydrophobic silica.

According to further embodiments, substantially anhydrous matrix carrierpharmaceutical composition may include molecules and/or particles havinghydrophilic properties. Non limiting examples are hydrophilic silica,water soluble vitamins, and the like.

According to further embodiments, the nanoparticles include silicananoparticles, and the size of the majority of the silica nanoparticlesmay be between 1-1000 nanometers. According to additional embodiments,the biopolymer may include a polysaccharide, saccharide, and/oroligosaccharide. The polysaccharide may include branched and/orunbranched and/or cyclic polysaccharides, wherein the polysaccharidesmay include such polysaccharide as, but not limited to: nutriose,maltsorb, beta-cycelodextrin, xylitol, mannitol, fiber, amylopectin,glucan, starch, glycogen and glycosaminoglycans (GAGs),mucopolysaccharides or derivatives thereof. According to furtherembodiments, a branched biopolymer may be used in the pharmaceuticalcomposition.

According to additional embodiments, the pharmaceutical composition mayfurther include a structural protein selected from the group consisting,for example, but not limited to: elastin, collagen, keratin, andfibrinogen. The pharmaceutical composition may further include an aminoacid selected from the group consisting of arginine, lysine, glutamicacid, aspartic acid and histidine. According to other embodiments, thepharmaceutical composition may further include an antioxidant.

According to other embodiments, the pharmaceutical composition mayfurther include one or more enhancers and/or targeting agents.

According to some embodiments, the pharmaceutical composition mayinclude more than one pharmaceutical agent and/or nutritional agent.

According to further embodiments, the process of the preparation of thematrix composition provides a formation of a complex, which includesnon-covalent bonds between hydrophobic surface of the nanoparticles(“First solid phase”), biopolymers (“Second solid phase”) and/or oilmolecules and hydrophobic surface of the pharmaceutical agent.

According to further embodiments the process of the preparation of thematrix provides a formation of a complex, which includes additionalnon-covalent bonds between hydrophilic surface of the pharmaceuticalagent, biopolymer (“Second solid phase”) and polar groups of the oils.

According to further embodiments, the matrix carrier composition mayfurther include hydrophilic nanoparticles and one or more additionalenhancers and/or targeting agents.

According to some embodiments, the volume ratio between the volume offirst solid phase and the volume of the second solid phase may be at adesired ratio so as to optimize the protecting properties of the matrixcarrier. The volume ratio may be determined according to the speed ofsound (c) of each solid phase. In some embodiments, the volume ratio maybe determined according to equation 1:V1×c1≦V2×c2  (equation 1);

-   -   wherein

V1 is the volume of the first solid phase;

c1 is the speed of sound in the first solid phase;

V2 is the volume of the second solid phase; and

c2 is the speed of sound in the second solid phase.

According to some embodiments the methods for the preparation of thematrix-carrier includes at least some of the following steps:

Activation of the second solid phase surface of matrix-carrier byadditional milling, vacuum treatment, chemical or ultra-sound cleaningor reduction; mixing one or more biopolymers with liquid oils undervacuum or in inert atmosphere; Inserting nanoparticles into oils andadditional vacuum treatment for removing air from the nanoparticlessurface; Inserting one or more pharmaceutical agents into pure oils,oils with hydrophobic nanoparticles or oils with biopolymer with orwithout the silica nanoparticles, depending on the physical properties(such as, for example, hydrophobicity, sensitivity to mechanical stress)of the pharmaceutical agent; Homogenization of the system while takinginto consideration the sensitivity of the active pharmaceutical tomechanical stress. The homogenization may be performed under inertatmosphere with controlled temperature, rate and time. Thehomogenization or mixing may aid in decreasing viscosity of theingredients and promote it's packing. In some embodiments, the order ofthe manufacturing steps may depend on the specific equipment used and/oron the properties of the pharmaceutical agent.

According to some embodiments there is provided a matrix carriercomposition for use in pharmaceutical delivery system, the compositioncomprising an intermolecular association of at least: a first solidphase comprising nanoparticles having hydrophobic surface, wherein thesize of the nanoparticles is in the range of about 5-1000 nm; a secondsolid phase, comprising a biopolymer having hydrophilic and hydrophobicparts; and a continuous phase comprising oil associated with said firstand said second solid phases.

According to some embodiments, the density of the first solid phase ishigher than 1.4 g/cm³. In some embodiments, the nanoparticles have asurface modified to be hydrophobic. The nanoparticles may be practicallyinsoluble in water. The nanoparticles may include silica nanoparticles.The nanoparticles may include fumed silica nanoparticles. Thenanoparticles may include zinc oxide nanoparticles. The nanoparticlesmay include carbon nanoparticles. The nanoparticles may include titaniumoxide nanoparticles. In some embodiments, the nanoparticles may includea mixture of nanoparticles selected from silica, zinc oxide, titaniumoxide, and carbon.

According to further embodiments, the biopolymer may be linear instructure, cyclic in structure and/or branched is structure. Thebiopolymer may include a saccharide. The biopolymer may include apolysaccharide. The polysaccharide may include starch, dextrin,cellulose, chitin, alpha glucan, beta glucan, amylopectin, glycogen,chitosan, cyclodextrin, mucopolysaccharide, or derivatives orcombination thereof. In some embodiments, the biopolymer includes astructural protein. The structural protein may include a high molecularweight structural protein. The structural protein may include a fibrousprotein. The structural protein may include a scleroprotein. Thestructural protein may include elastin, collagen, keratin, fibrinogen orany combination thereof.

According to further embodiments, the oil may include one or morenaturally-occurring oils. The oil may include non-polar oil having polarregions. In some embodiments, the oil is selected from a groupconsisting of sesame oil, olive oil, linseed oil, evening primrose oil,silicone oil, and sea buckthorn oil, palm oil, or any combinationthereof. In some embodiments, the oil may be selected from a groupconsisting of sunflower oil, corn oil, soybean oil, jojoba oil, marrowoil, grapeseed oil, hazelnut oil, apricot oil, macadamia oil, palm oil,almond oil, castor oil, and the like, or any combination thereof. Insome embodiments, the oil may include lanolin. In some embodiments, theoil may include a synthetic oil. In some embodiments, the oil mayinclude one or more naturally-occurring oils, one or more synthetic oil,or any combination thereof. In some embodiments, the oil may include afatty alcohol. The oil may be 2-octyldodecanol. The oil may be selectedfrom a fatty acid ester and a phenylsilicone. The oil may be selectedfrom phenyltrimethicones, diphenyldimethicones, andpoly-methylphenylsiloxanes. In some embodiments, oil is at least onewax. In some embodiments, the oil may include oblepicha oil, jojoba oil,olive oil or combinations thereof. In some embodiments, the oil mayinclude olive oil, linseed oil, oblepicha oil, sesame oil, palm oil orcombinations thereof. In some embodiments, the oil may include jojobaoil, oblepicha oil, sesame oil, olive oil or combinations thereof. Insome embodiments, the oil may include wax, jojoba oil, oblepicha oil,sesame oil, olive oil or combinations thereof. In some embodiments, theoil may include linseed oil, oblepicha oil, olive oil, palm oil orcombinations thereof.

According to further embodiments, the composition may further include atleast one anti-oxidant. The antioxidant may include beta-carotene.

According to further embodiments, the composition may further include anamino acid selected from the group consisting of arginine, lysine,glutamic acid, aspartic acid and histidine and combinations andderivatives thereof.

According to additional embodiments, the volume ratio between the firstsolid phase and the second solid phase is determined according toequation 1:V1×c1≦V2×c2  (equation 1);

wherein

V1 is the volume of the first solid phase;

c1 is the speed of sound in the first solid phase;

V2 is the volume of the second solid phase; and

c2 is the speed of sound in the second solid phase.

According to some embodiments the composition may further include atleast one active pharmaceutical agent. The composition may furtherinclude an enhancer. The composition may further include a targetingagent. The composition may further include at least one nutritionalagent.

According to some embodiments, the composition may be adapted for oraladministration.

According to additional embodiments, the composition may be adapted forparenteral administration.

According to some embodiments, there is provided a method formanufacturing a matrix carrier composition for use in a pharmaceuticalcomposition, the method includes: mixing a first solid phase with anoil, wherein the first solid phase comprises nanoparticles havinghydrophobic surface and particle size of about 5-1000 nm; activating asecond solid phase, wherein the second solid phase comprises abiopolymer having hydrophilic and hydrophobic parts; adding theactivated second solid phase into an oil; and mixing the oil comprisingthe first solid phase and the oil comprising the activated second solidphase.

In some embodiments, activating includes milling, vacuum treatment,chemical treatment, ultrasonic treatment or any combination thereof.

In some embodiments, one or more steps of the method may be performedunder vacuum or in an inert atmosphere.

In some embodiments, the method may further include homogenization ofthe mixture of the oil comprising the first solid phase and the oilcomprising the activated second solid phase.

In some embodiments, the method may further include maturation of thematrix carrier composition for about 1 to 72 hours. The maturation maybe performed at a temperature in the range of about 1-25° C.

In addition to the exemplary aspects and embodiments described above,further aspects and embodiments will become apparent by reference to thefigures and by study of the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments are illustrated in referenced figures. Dimensionsof components and features shown in the figures are generally chosen forconvenience and clarity of presentation and are not necessarily shown toscale. It is intended that the embodiments and figures disclosed hereinare to be considered illustrative rather than restrictive. The figuresare listed below.

FIG. 1: LC/MS chromatograms of Insulin samples within and without aMatrix Carrier formulation, according to some embodiments.

FIGS. 2A-B: Graphs depicting glucose levels (mg/dL) and the levels ofinsulin over time (hours) in blood of rats injected with various insulinformulations.

DETAILED DESCRIPTION

According to some embodiments there is provided a matrix carriercomposition for use in a pharmaceutical composition/pharmaceuticaldelivery system, with a pharmaceutical agent. The matrix comprises anintermolecular association of at least: a first solid phase, whichpreferably includes nanoparticles with size in range 5-1000 nm havinghydrophobic surface; a second solid phase, preferably a biopolymerhaving both hydrophilic and hydrophobic ends; and a Continuous phase ofoil associated with the components of the composition.

According to some embodiments, the second solid phase is comprised ofbiopolymer that may be linear, branched, cyclic or any combinationthereof.

In some embodiments, the pharmaceutical agent may include apharmaceutical drug (a substance intended for use in the medical cure,treatment, prevention and/or diagnosis of health related condition). Insome embodiments, the pharmaceutical agent is a nutritional agent (apreparation intended to supplement a diet and provide nutrients, suchas, for example, vitamins, minerals, fiber, fatty acids, or amino acids,that may be missing or may not be consumed in sufficient quantity in aperson's diet). In some embodiments, the pharmaceutical agent is acosmetic agent (an agent used to treat, prevent, cosmetic relatedconditions).

In some embodiments, the matrix carrier compositions for use in adelivery system are suitable for oral administration. In someembodiments, the matrix carrier compositions for use in a deliverysystem are suitable for parenteral administration.

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

As used herein, the terms “non-covalent interaction”, “non-covalentbond”, and “non-covalent forces” may be used interchangeably and referto the interaction, also referenced as association, of a first substanceand a second substance wherein a covalent bond is not formed between thetwo substances. Non-limiting, representative interactions are van derWaals interactions, hydrogen bonding, and electrostatic interactions(also called ionic bonding).

As used herein, the terms “treating” and “treatment” with respect to adisease or condition, refer to taking steps to obtain beneficial ordesired results, including but not limited to, alleviation oramelioration of one or more symptoms of the disease or condition,diminishment of extent of the disease or condition, prevention of theonset of the disease or condition, delay or slowing of progression,amelioration, palliation or stabilization of the disease or condition,partial or complete remission, prolonged survival and other beneficialresults known in the art.

As used herein, the term “pharmaceutical agent” is directed to anysubstance, molecule, and like, which may have an effect on one or morehealth and/or nutritional and/or cosmetic related conditions. In someembodiments, a pharmaceutical agent may include a “pharmaceutical drug”or a combination of pharmaceutical drugs. The term “pharmaceutical drug”(interchangeably referred to herein as “drug”) refers to a substancewhich may be intended for use in the medical cure, treatment, preventionand/or diagnosis of a health related condition (such as, for example, adisease). The term “pharmaceutical drug” is intended to includesubstances having pharmacological and/or pharmaceutical, and/orbiological activity. In some embodiments, the pharmaceutical agent mayinclude a nutritional agent or a combination of nutritional agents. Theterm “nutritional agent” refers to a substance intended to supplement adiet and provide nutrients, such as, for example, vitamins, minerals,fiber, fatty acids, or amino acids, that may be missing or may not beconsumed in sufficient quantity in the diet. In some embodiments, thepharmaceutical agent may include a cosmetic agent or a combination ofcosmetic agents. The term cosmetic agent refers to a substance used totreat and/or prevent, cosmetic related conditions. In some embodimentsthe pharmaceutical agent may include any combination of a pharmaceuticaldrug, a nutritional agent, and/or a cosmetic agent.

As used herein, the terms “pharmaceutical composition”, “deliverysystem” and “pharmaceutical delivery system” may interchangeably byused. The terms refer to any applicable type of deliverysystem/pharmaceutical composition that may be used with the matrixcarrier of the present disclosure to deliver a pharmaceutical agent (asdefined herein).

As used herein, “intimate mixture” refers to a physical mixture of atleast two components which are in direct physical contact with eachother. For example, one component may coat the other component or onecomponent may adhere directly to the outer surface of the particlecomprising the other component. Alternately, the material of onecomponent may be intermingled or intertwined with the other component.

As used herein, the term “potency” refers to the dose of pharmaceuticalagent required to produce a specific effect of given intensity ascompared to standard reference. Potency is a comparative rather than anabsolute expression of the agent activity. Drug potency depends onvarious factors, such as one or more of bioavailability, targeting,lifetime in body fluid circulation and efficacy.

As used herein, “ADME” is an acronym in pharmacokinetics andpharmacology for Absorption, Distribution, Metabolism, and Excretion ofan administered pharmaceutical drug, and describes the disposition of apharmaceutical drug (compound) within an organism. All four ADMEcriteria may influence the drug levels and kinetics of drug exposure tothe tissues and hence may influence the performance and pharmacologicalactivity of the compound as a drug. Absorption may determine thecompound's bioavailability whereas the drug's half life is determined byits distribution, metabolism, and removal from the body via excretion.

As used herein, the term “bioavailability” refers to the fraction of anadministered dose of intact drug that reaches the systemic circulation.Bioavailability is largely determined by the properties of the dosageform, rather than by the pharmaceutical agent's physiochemicalproperties, which determine absorption potential. By definition, when adrug is administered intravenously (IV), its bioavailability is 100%.When a drug is orally administered, its bioavailability typicallydecreases.

Age, gender, physical activity, genetic phenotype, stress, disorders(such as, for example, achlorhydria and malabsorption syndromes),previous GI surgery (eg, bariatric surgery), and the like, may alsoaffect drug bioavailability. Chemical reactions that reduce absorptioncan reduce bioavailability. Such reactions include, for example,formation of a complex (for example between tetracycline and polyvalentmetal ions), hydrolysis by gastric acid or digestive enzymes (forexample, penicillin and chloramphenicol palmitate hydrolysis),conjugation in the intestinal wall (for example, sulfoconjugation ofisoproterenol), adsorption to other drugs (for example, digoxin tocholestyramine), and metabolism by luminal microflora.

As used herein, the term “half life” refers to the duration of action ofa drug, i.e., the period of time required for the concentration oramount of drug in the body to be reduced by one-half. A drug moleculethat leaves plasma may have one or more of several fates. For example,the drug molecule can be eliminated from the body by the kidneys or bythe liver. The removal of a drug from the plasma is known as clearance,and the distribution of the drug in the various body tissues is known asthe volume of distribution. Both of those pharmacokinetic parameters arerelated to the determination of the half life of a drug.

“Branched” as used herein encompasses both biopolymers that arenaturally branched and those engineered to be branched by at least onephysical treatment, such as thermal and ultrasound treatments.“Branched” is also intended to encompass biopolymers wherein asubstituent of a monomer subunit of the biopolymer is replaced byanother covalently bonded chain of the biopolymer. In some embodiments,the branched biopolymer is crosslinked. In some embodiments, thebranched biopolymer is not crosslinked.

As used herein, the term “saccharide” refers to any simple carbohydrateincluding monosaccharides, monosaccharide derivatives, monosaccharideanalogs, and sugars, including those which form the individual units ina polysaccharide. As used herein, the term “monosaccharide” refers topolyhydroxyaldehyde (aldose) or polyhydroxyketone (ketose) andnon-polysaccharide derivatives and analogs thereof. As used herein, theterm “polysaccharide” refers to polymers formed from about 500 to over100,000 saccharide units linked to each other by hemiacetal orglycosidic bonds. The polysaccharide may be either straight chain,singly branched, or multiply branched wherein each branch may haveadditional secondary branches, and the monosaccharides may be standardD- or L-cyclic sugars in the pyranose (6-membered ring) or furanose(5-membered ring) forms such as D-fructose and D-galactose,respectively, or they may be cyclic sugar derivatives, for example aminosugars such as D-glucosamine, deoxy sugars such as D-fucose orL-rhamnose, sugar phosphates such as D-ribose-5-phosphate, sugar acidssuch as D-galacturonic acid, or multi-derivatized sugars such asN-acetyl-D-glucosamine, N-acetylneuraminic acid (sialic acid), orN-sulfato-D-glucosamine. When isolated from nature, polysaccharidepreparations comprise molecules that are heterogeneous in molecularweight. Non-limiting examples of polysaccharides include, among othercompounds, galactomanans and galactomannan derivatives;galacto-rhamnogalacturons and galacto-rhamnogalacturon derivatives, andgalacto-arabinogalacturon and galacto-arabinogalacturon derivatives.

As used herein, the term “beta-glucan” refers to those polysaccharideswhich comprise D-glucopyranosyl units which are linked together by (1→3)or (1→4) beta-linkages. Beta-Glucans occur naturally in many cerealgrains such as oats and barley. The molecular weight of beta-glucanmolecules occurring in cereals is, for example, from 200 to 2000 kDa.

As used herein, the term “dextrin” refers to a low-molecular-weightcarbohydrate produced by the hydrolysis of starch. In some embodiments,the term refers to a linear α-(1,4)-linked D-glucose polymer startingwith an α-(1,6) bond or a mixture of same. Dextrins are widelycommercially available and can be produced inter alia by digestion ofbranched amylopectin or glycogen with α-amylase. A non-limiting exampleof a dextrin is a maltodextrin. But there are many different types ofdextrin known, and those different types can be used in otherembodiments.

As used herein, the term “fibrous polymer” refers to a polymer in theform of a network of discrete thread-shaped pieces. As used herein, theterms “fiber” and “dietary fiber” refer to compounds, including but notlimited to indigestible residue, plant cell polysaccharides, and lignin,all of which are resistant to hydrolysis by human digestive enzymes.Non-limiting examples of fibers are members selected from guar gum,pectin, fructo-oligosaccharides and derivatives thereof. Small amountsof other indigestible compounds, such as phytates, tannins, saponins andcutin, may be included in dietary fiber since these compounds areindigestible and associated with dietary fiber polysaccharides.

As used herein, “silica” refers to silicon dioxide. Silica is widelyrecognized as a safe food additive (Thirteenth report of the JointFAO/WHO Expert Committee on Food Additives, FAO Nutrition MeetingsReport Series; from the Joint FAO/WHO Expert Committee on Food Additivesmeeting in Rome, May 27-Jun. 4, 1969).

As used herein, the term “silicate” refers to a compound containingsilicon and oxygen, e.g. in tetrahedral units of SiO4. In otherembodiments, the term refers to a compound containing an anion in whichat least one central silicon atom is surrounded by electronegativeligands. Non-limiting, representative examples of silicates arehexafluorosilicate, sodium silicate (Na2SiO3), aluminum silicates, andmagnesium silicates.

As used herein, the term “wax” means a lipophilic compound, which issolid at room temperature (25° C.), with a reversible solid/liquidchange of state, having a melting point of greater than or equal to 30°C., which may be up to 120° C.

In some embodiments, the present invention provides a matrix carriercomposition, which includes pharmacologically inert nanoparticles, innon-covalent association with a biopolymer and a lipid comprisingnon-polar and polar bonds, with pharmaceutical agent, wherein the inertnanoparticles include silica nanoparticles, and wherein the diameter ofthe nanoparticles is between 1-1000 nanometers, and wherein thebiopolymer includes a combination of branched and non-branchedbiopolymers, and wherein the lipid includes a mix of the syntheticand/or natural saturated and unsaturated fatty acids which associatedwith nanoparticles, biopolymer or carbohydrate and includingpharmaceutical agent and in some embodiments enhancer and or targetingagent. Each possibility represents a separate embodiment of the presentinvention.

In some embodiments, the present invention provides a matrix carriercomposition, comprising pharmacologically inert nanoparticles, innon-covalent association with a biopolymer, wherein the inertnanoparticles includes silica nanoparticles, and wherein the diameter ofthe nanoparticles is between 1-1000 nanometers, and thenanoparticle-biopolymer complex is associated with the oil, and whereinthe particle diameter of the matrix carrier composition is between100-500,000 nanometers (nm). In certain preferred embodiments, theparticle diameter of the matrix carrier composition is between100-50,000 nm. In another embodiment, the oil phase of the matrixcarrier composition comprises a plurality of oils. Each possibilityrepresents a separate embodiment of the present invention.

In another embodiment, the matrix carrier composition is held togetherby non-covalent forces. In another embodiment, without wishing to bebound by any theory or mechanism of action, the non-covalent forcesbetween the components of the matrix composition enable the matrixcomposition to self-assemble when the components are mixed together, asdescribed herein. In another embodiment, without wishing to be bound byany theory or mechanism of action, the matrix carrier includes two solidphases containing at least two solid pharmacologically inert materials(nanoparticles and biopolymers) with different properties. In anotherembodiment, the non-covalent forces cause the nanoparticles andbiopolymer to form a mixture. In another embodiment, the matrixcomposition exhibits an ordered, fractal structure. Each possibilityrepresents a separate embodiment of the present invention. The structureand composition of the matrix carrier may allow the use of the matrixcarrier in various administration routes, such as, for example by oraladministration, by parenteral routes, topical, and the like.

In another embodiment, without wishing to be bound by any theory ormechanism of action, the energy of non-covalent bonds between apharmaceutical agent and the matrix carrier may be less than about 10kcal per mole (such as in the range of about 1 to 5 kcal per mole). Thisvalue is higher than the energy of thermal fluctuations at 37° C. (about0.615 kcal per mole), which is enough for keeping or protection thepharmaceutical agent in gastro-intestinal tract. This energy isrelatively close, for example, to the bond energy between insulin andits receptor. This may provide a possible control of pharmacokineticsand pharmacodynamics of the pharmaceutical agent. In some embodiments,the matrix carrier may provide protection from biodegradation of thepharmaceutical agent at 37° C. in the stomach (acid solution of pepsinand other enzymes) and small intestine (neutral solution of thepancreatic enzymes, bile acids salts, etc) for more than 8 hours.

In some embodiments, the matrix carrier may release the pharmaceuticalagents due to action of synthetic surfactants (such as, for example,TWEEN 20, TWEEN 80, and the like) or natural surfactants of body fluids(such as, for example, blood, lymph, interstitial fluid, and the like).

In another embodiment, the nanoparticle-biopolymer complex is dispersedwithin the oil phase of the matrix composition. In another embodiment,the oil phase is impregnated with the nanoparticle-biopolymer complex ofthe matrix composition. As provided herein, the present inventionprovides compositions wherein the nanoparticles and biopolymer form amatrix that is impregnated and completely surrounded by the oil phase.Each possibility represents a separate embodiment of the presentinvention.

Oil having particulate matter associated therewith refers to particulatematter that is in contact with oil. For example “associated with” mayinclude embedded, dispersed, immersed, suspended, and the like, withinthe oil. The composition as a whole need not be homogeneous with regardto the distribution of the particulate matter. Rather, the particulatematter is capable of being embedded, dispersed, immersed, suspended, andthe like, in the oil when agitated. The particulate matter need not becompletely homogeneous, but rather is characterized by its containingthe ingredients specified herein and its contact with the oil of thepresent invention. Compositions wherein the particulate matter isagglomerated fall within the scope of the present invention

The Matrix Carrier Composition

According to some embodiments, there is provided a matrix carriercomposition for use in a pharmaceutical composition for administration,comprising an intermolecular association of at least one biopolymer,nanoparticles, and at least one oil. Administration may include variousadministration routes, such as, for example, but not limited to: oraladministration, parenteral administration, topical administration, andthe like.

That intermolecular association may take place spontaneously and resultin the formation of stable structures. The course of that associationprocess, and properties of the resulting product, may depend upon thenature of the components and/or upon the conditions under which theassociation takes place.

According to some embodiments, the volume ratio between the first solidphase and the volume of the second solid phase may be at a desired ratioso as to optimize the protecting properties of the matrix carrier.

The ratio of the volume of the first solid phase and the volume of thesecond solid phase may be determined according to the speed of sound (c)of each solid phase as following:

Speed of sound (c) in the material is a function of its density:c=√C/ρ;Wherein c—is Speed of sound; C—coefficient of stiffness; ρ—density

The Second and First Solid phase volume ratio may thus be calculatedaccording to the following equation (equation 1):V1×c1≦V2×c2  (Equation 1);wherein V1—volume of the First Solid Phase; c1—Speed of Sound in theFirst Solid Phase; V2—volume of the Second Solid Phase; c2—Speed ofSound in the Second Solid Phase.

In some embodiments, that intermolecular association comprises a networkof non-covalent interactions between the at least one biopolymer, thenanoparticles, and the at least one oil. That is, the recited componentsmay be held together by non-covalent forces. In some embodiments,without wishing to be bound by any theory or mechanism of action, thenon-covalent forces enable the components to self-assemble when thecomponents are blended together. In some embodiments, again withoutwishing to be bound by any theory or mechanism of action, thenon-covalent forces cause the nanoparticles and biopolymer to form anintimate mixture. In some embodiments, again without wishing to be boundby any theory or mechanism of action, the association results in anordered, fractal structure.

In some embodiments, without wishing to be bound by any theory ormechanism of action, matrix carrier compositions described herein may beconverted in the digestive system to particles smaller in size butsimilar in structure to the original composition, which are absorbedsimilarly to fat drops and like chylomicrons reach the bloodstream withor without undergoing first-pass metabolism in the liver.

In some embodiments, without wishing to be bound by any theory ormechanism of action, the energy of non-covalent bonds between apharmaceutical agent and the matrix carrier may be less than about 10kcal per mole (such as in the range of about 1 to 5 kcal per mole). Thisvalue is higher than the energy of thermal fluctuations at 37° C. (about0.615 kcal per mole), which is enough for keeping or protection thepharmaceutical agent in gastro-intestinal tract. This energy isrelatively close, for example, to the bond energy between insulin andits receptor. This may provide a possible control of pharmacokineticsand pharmacodynamics of the pharmaceutical agent. In some embodiments,the matrix carrier may provide protection from biodegradation of thepharmaceutical agent at 37° C. in the stomach (acid solution of pepsinand other enzymes) and small intestine (neutral solution of thepancreatic enzymes, bile acids salts, and the like) for more than 2hours. In some embodiments matrix carrier provides protection for morethan 4 hours, more than 6 hours, more than 8 hours, more than 12 hours,more than 16 hours. In some embodiments, the matrix carrier may releaseand preserve the activity of the pharmaceutical agent after treatment bysurfactants which, may cause disassembly of the matrix complex,associated by non-covalent bonds (as further demonstrated in Example 7).

According to some embodiments, without wishing to be bound by any theoryor mechanism of action, the matrix carrier compositions described hereinmay provide protection of the pharmaceutical agent from the externalenvironment. In some embodiments, the matrix carrier compositionsdescribed herein may enable oral delivery of the pharmaceutical agent.In some embodiments, the matrix carrier compositions described hereinmay modulate the pharmacokinetics and/or pharmacodynamics ofpharmaceutical agents administered by oral and/or parenteral route, ascompared to other administration routes and/or use of otherpharmaceutical compositions and formulations.

In some embodiments, the intermolecular association comprises a networkof non-covalent interactions between the at least one biopolymer, thenanoparticles, and the at least one oil, wherein there is additionallyone or more covalent bonds between the at least one biopolymer and thenanoparticles, and/or between the at least one biopolymer and the atleast one oil, and/or between the at least one at least one oil and thenanoparticles. For example, in some embodiments, at least a portion ofthe at least some of the nanoparticles, and more particularly, silicananoparticles, is covalently bonded to the biopolymer, according tomethods known by those skilled in the art.

In some embodiments, the biopolymer and/or the nanoparticles aredispersed within the at least one oil. In some embodiments, thebiopolymer and/or the nanoparticles are suspended in the at least oneoil. In some embodiments, the biopolymer and/or the nanoparticles areembedded within the at least one oil. In some embodiments, the at leastone oil is impregnated with the biopolymer and/or the nanoparticles. Insome embodiments, the associated nanoparticles and biopolymer form amatrix that is impregnated and surrounded by the at least one oil. Insome embodiments, the nanoparticles and biopolymer are otherwiseassociated with the at least one oil.

In some embodiments there is provided a matrix carrier pharmaceuticalcomposition with a pharmaceutical agent, the matrix comprises anintermolecular association of at least:

-   -   1. First solid phase, preferably nanoparticles with size in        range 5-1000 nm having hydrophobic surface;    -   2. Second solid phase, preferably biopolymer having both        hydrophilic and hydrophobic parts; and    -   3. Continuous phase of oil associated with the components of the        matrix carrier pharmaceutical composition.

According to some embodiments, the matrix carrier composition need notbe homogeneous, but rather may be characterized by its containing theingredients specified herein.

According to some embodiments, the matrix carrier composition issuspension. In some embodiments, the matrix carrier composition isemulsion. In some embodiments, the matrix carrier forms in waterenvironment a water based emulsion wherein non-polar phase issuspension.

In some embodiments, the matrix carrier composition is agglomerated.

In some embodiments the weight of the at least one biopolymer may be atleast equal to that of the nanoparticles. In some embodiments, theweight of the at least one biopolymer may be greater than the weight ofthe nanoparticles. In some embodiments the weight of the at least onebiopolymer may be at least twice that of the nanoparticles. In someembodiments the weight of the at least one biopolymer may be fivefoldthat of the nanoparticles. In some embodiments the weight of the atleast one biopolymer may be at least ten times greater than the weightof nanoparticles. In some embodiments the at least one biopolymer may beat least one hundred times greater than the weight of nanoparticles.

In some embodiments, the matrix carrier comprises an intermolecularassociation of at least one biopolymer, silica nanoparticles, and atleast one oil.

In some embodiments, the matrix carrier comprises an intermolecularassociation of at least one biopolymer comprising a polysaccharide,nanoparticles, and at least one oil.

In some embodiments, the matrix carrier comprises an intermolecularassociation of at least one biopolymer comprising a branchedpolysaccharide, silica nanoparticles, and at least one oil.

In some embodiments, the matrix carrier comprises an intermolecularassociation of at least one biopolymer comprising a branchedpolysaccharide, nanoparticles, and at least one oil.

In some embodiments, the matrix carrier composition is not composed ofsilica nanoparticles having a hydrophobic surface, a polysaccharide, andat least one oil.

In some embodiments, when the matrix carrier composition is to be usedfor the oral administration of insulin, the matrix carrier compositionis not composed of olive oil, a dietary fiber, silica nanoparticles,oblepicha oil, and sesame oil. In some embodiments, when the matrixcarrier composition is to be used for the oral administration ofinsulin, the matrix carrier composition is not composed of olive oil,rice polysaccharides, silica nanoparticles, oblepicha oil, and eveningprimrose oil. In some embodiments, when the matrix carrier compositionis to be used for the oral administration of insulin, the matrix carriercomposition is not composed of olive oil, a dietary fiber, silicananoparticles, oblepicha oil, evening primrose oil, and linseed oil. Insome embodiments, when the matrix carrier composition is to be used forthe oral administration of insulin, the matrix carrier composition isnot composed of olive oil, a dietary fiber, oblepicha oil, silicananoparticles, and sesame oil. In some embodiments, when the matrixcarrier composition is to be used for the oral administration ofinsulin, the matrix carrier composition is not composed of olive oil,oblepicha oil, sesame oil, amylopectin, chitin, and silicananoparticles. In some embodiments, when the matrix carrier compositionis to be used for the oral administration of insulin, the matrix carriercomposition is not composed of olive oil, rice polysaccharides, silicananoparticles, oblepicha oil, and sesame oil. In some embodiments, whenthe matrix carrier composition is to be used for the oral administrationof insulin, the matrix carrier composition is not composed of olive oil,a dietary fiber, oblepicha oil, silica nanoparticles, and sesame oil. Insome embodiments, when the matrix carrier composition is to be used forthe oral administration of insulin, the matrix carrier composition isnot composed of olive oil, rice polysaccharides, silica nanoparticles,oblepicha oil, and evening primrose oil. In some embodiments, when thematrix carrier composition is to be used for the oral administration ofinsulin, the matrix carrier composition is not composed of olive oil,oblepicha oil, sesame oil, amylopectin, chitin, and silicananoparticles.

In some embodiments, when the matrix carrier composition is to be usedfor the oral administration of erythropoietin, the matrix carriercomposition is not composed of olive oil, rice polysaccharides, silicananoparticles, oblepicha oil, and linseed oil.

In some embodiments, when the matrix carrier composition is to be usedfor the oral administration of growth hormone, the matrix carriercomposition is not composed of amylopectin from maize, silicananoparticles, olive oil, oblepicha oil, and sesame oil.

In some embodiments, when the matrix carrier composition is to be usedfor the oral administration of copaxone, the matrix carrier compositionis not composed of jojoba oil, olive oil, alpha-glucan, beta-glucan,amylopectin, silica nanoparticles, oblepicha oil, and sesame oil.

In some embodiments, when the matrix carrier composition is to be usedfor the oral administration of copaxone, the matrix carrier compositionis not composed of oblepicha oil, olive oil, beta-glucan, amylopectin,silica nanoparticles, and beeswax.

In some embodiments, when the matrix carrier composition is to be usedfor the oral administration of Apolipoprotein A-mimetic peptide, thematrix carrier composition is not composed of oblepicha oil, olive oil,beta-glucan, chitin, amylopectin, silica nanoparticles, and beeswax.

In some embodiments, when the matrix carrier composition is to be usedfor the oral administration of Rituxan, the matrix carrier compositionis not composed of oblepicha oil, olive oil, chitin, amylopectin, silicananoparticles, and beeswax.

In some embodiments, when the matrix carrier composition is to be usedfor the oral administration of DNase, the matrix carrier composition isnot composed of jojoba oil, oblepicha oil, rice polysaccharides, silicananoparticles, olive oil, and sesame oil. In some embodiments, when thematrix carrier composition is to be used for the oral administration ofDNase, the matrix carrier composition is not composed of jojoba oil,oblepicha oil, a dietary fiber, silica nanoparticles, olive oil, andsesame oil.

In some embodiments, when the matrix carrier composition is to be usedfor the oral administration of RNase, the matrix carrier composition isnot composed of rice polysaccharides, silica nanoparticles, linseed oil,oblepicha oil, olive oil, sesame oil, L-glutamic acid, glycine,L-lysine, and L-arginine.

In some embodiments, when the pharmaceutical agent is a protein orpeptide having therapeutic activity, the pharmaceutical composition isnot composed of silica nanoparticles having a hydrophobic surface, apolysaccharide, and at least one oil.

In some embodiments, the pharmaceutical agent is not a protein orpeptide having therapeutic activity.

First Solid Phase—Nanoparticles

The nanoparticles generally will have a surface capable of forming anintermolecular association with the at least one biopolymer with theoil. In some embodiments, the nanoparticles have a hydrophobic surface.Reference to a “hydrophobic” surface indicates, in some embodiments,that at least 40% of the nanoparticle surface is hydrophobic (forexample, at least 50%, 50-60%, 60-70%, or 70-100%), with the remainderof the surface being non-hydrophobic.

In some embodiments, the nanoparticles have a surface modified to behydrophobic, and in some of those embodiments at least 40% of thenanoparticle surface is hydrophobic (for example, at least 50%, 50-60%,60-70%, or 70-100%), with the remainder of the surface beingnon-hydrophobic. In some embodiments, the nanoparticles are modified bycoating the surface with a hydrocarbon. In some embodiments, the coatingcauses the nanoparticles to display hydrocarbon moieties on theirsurface. In some embodiments, the hydrocarbon moieties are selected frommethyl, ethyl, propyl, isopropyl, butyl, isobutyl, T-butyl, pentyl, andiso-pentyl. In some embodiments, the coating causes the nanoparticles todisplay methyl moieties on their surface.

In some embodiments, the nanoparticles are silica nanoparticles, whichuse is known in the art, as disclosed, for example, in U.S. Pat. Nos.6,322,765 and 6,698,247.

In some embodiments the inert nanoparticles include silicananoparticles, where at least 80% of silica is hydrophobic silica. Insome embodiments the inert nanoparticles include silica nanoparticles,where at least 90% of silica is hydrophobic silica. In some embodimentsthe inert nanoparticles include silica nanoparticles, where at least 95%of silica is hydrophobic silica.

In some embodiments, the density of the first solid phase may be higherthan 1.2 g/cm³. In some embodiments, the density of the first solidphase may be higher than 1.3 g/cm³. In some embodiments, the density ofthe first solid phase may be higher than 1.4 g/cm³. In some embodiments,the density of the first solid phase may be higher than 1.5 g/cm³.

Methods for imparting a hydrophobic surface to nanoparticles arewell-known in the art, and are also described herein. In someembodiments, the surface of the nanoparticle, e.g., when thenanoparticle comprises fumed silica, may be chemically modified todecrease the number of silanol groups. For example, silanol groups canbe substituted with hydrophobic groups to obtain a hydrophobic silica.The hydrophobic groups can be:

trimethylsiloxy groups, which are obtained, for example, by treatment offumed silica in the presence of hexamethyldisilazane. Silicas thustreated are known as “silica silylate” according to the CTFA (6thedition, 1995). They are sold, for example, under the references“Aerosil R812®” by the company Degussa and “CAB-OSIL TS-530®” by thecompany Cabot; dimethylsilyloxy or polydimethylsiloxane groups, whichare obtained, for example, by treatment of fumed silica in the presenceof polydimethylsiloxane or dimethyldichlorosilane. Silicas thus treatedare known as “silica dimethyl silylate” according to the CTFA (6thedition, 1995). They are sold, for example, under the references“Aerosil R972®.”, “Aerosil R974®” by the company Degussa, “CAB-O-SILTS-610®.” and “CAB-O-SIL TS-720®”, by the company Cabot.

Other methods for imparting a hydrophobic surface to nanoparticles arewell-known in the art and are described in various documents, such as,for example: Chung et al (Hydrophobic modification of silicananoparticle by using aerosol spray reactor. Colloids and Surfaces A:Physicochem. Eng. Aspects 236 (2004) 73-79); Fu X, et. al. (Physicochem.Eng. Aspects 179: 65, 2001); Krysztafkiewicz A, et. al. (Colloids Surf.A: Physicochem. Eng. Aspects 173:73, 2000); Jean J and Yang S, J (Am.Ceram. Soc. 83(8):1928, 2000); Zhang J and Gao L. (Ceram. Int. 27: 143,2001); US Patent applications: US 2007/0172426, US 2006/0053971, US2007/0098990.

In some embodiments, the nanoparticles are practically insoluble inwater. “Practically insoluble” refers, in some embodiments, to asubstance having a solubility of less than 100 parts per millionweight/weight (ppm). In some embodiments, the term refers to asolubility of less than 200 ppm. In some embodiments, the term refers toa solubility of less than 80 ppm. In some embodiments, the term refersto a solubility of less than 60 ppm. In some embodiments, the termrefers to a solubility of less than 50 ppm. In some embodiments, theterm refers to a solubility of less than 40 ppm. In some embodiments,the term refers to a solubility of less than 30 ppm. In someembodiments, the term refers to a solubility of less than 20 ppm. Insome embodiments, the term refers to a solubility of less than 15 ppm.In some embodiments, the term refers to a solubility of less than 10ppm.

In some embodiments, the nanoparticles are pharmacologically inert. Insome embodiments, the nanoparticles are composed of materials that aregenerally recognized as safe (GRAS). In some embodiments, thenanoparticles are non-toxic. In some embodiments, the nanoparticles arenon-teratogenic. In some embodiments, the nanoparticles are biologicallyinert.

In some embodiments, the nanoparticles comprise silica nanoparticles. Insome embodiments, the nanoparticles comprise fumed silica nanoparticles.

“Silica nanoparticles” refers, for example, to nanoparticles selectedfrom silica, silicates, and combinations thereof.

Silica nanoparticles are available commercially, e.g. as 99.99% purefinely ground silica. It will be understood by those skilled in the artthat lower grades of purity of silica may be used.

In some embodiments, the nanoparticles are a single type. In someembodiments, the nanoparticles are of multiple types. In someembodiments, the nanoparticles are a mixture of silica nanoparticles andother types of nanoparticles. In some embodiments, essentially all thenanoparticles are silica nanoparticles.

In some embodiments, the nanoparticles comprise zinc oxidenanoparticles.

In some embodiments, the nanoparticles comprise carbon nanoparticles.

In some embodiments, the nanoparticles comprise titanium oxidenanoparticles.

In some embodiments, the nanoparticles comprise nanoparticles other thansilica nanoparticles but having a hardness similar to that of silicananoparticles.

In some embodiments, the nanoparticles comprise a mixture ofnanoparticles selected from silica, zinc oxide, titanium oxide, andcarbon.

In some embodiments, the nanoparticles comprise silver nanoparticlesand/or compound silver nanoparticles.

In some embodiments, the nanoparticles comprise gold nanoparticlesand/or compound gold nanoparticles.

In some embodiments, the nanoparticles comprise platinum nanoparticlesand/or compound platinum nanoparticles.

In some embodiments, the nanoparticles comprise a mixture ofnanoparticles selected from gold, platinum and silver and anycombination or compounds thereof.

In some embodiments, the mean diameter of the nanoparticles is from 1 to800 nanometers (nm). In some embodiments, the mean diameter is from 2 to400 nm. In some embodiments, the mean diameter is from 2 to 300 nm. Insome embodiments, the mean diameter is from 3 to 200 nm. In someembodiments, the mean diameter is from 4 to 150 nm. In some embodiments,the mean diameter is from 4 to 100 nm. In some embodiments, the meandiameter is from 1 to 100 nm. In some embodiments, the mean diameter isfrom 5 to 50 nm. In some embodiments, the mean diameter is from 5 to 40nm. In some embodiments, the mean diameter is from 5 to 30 nm. In someembodiments, the mean diameter is from 7 to 40 nm. In some embodiments,the mean diameter is from 6 to 25 nm. In some embodiments, the meandiameter is from 10 to 11 nm. In some preferred embodiments, the meandiameter of the nanoparticles is from 5 to 600.

In some embodiments, the average diameter is about 5 nm. In someembodiments, the average diameter is about 6 nm. In some embodiments,the average diameter is about 7 nm. In some embodiments, the averagediameter is about 8 nm. In some embodiments, the average diameter isabout 9 nm. In some embodiments, the average diameter is about 10 nm. Insome embodiments, the average diameter is about 12 nm. In someembodiments, the average diameter is about 14 nm. In some embodiments,the average diameter is about 16 nm. In some embodiments, the averagediameter is about 18 nm. In some embodiments, the average diameter isabout 20 nm. In some embodiments, the average diameter is anotherdiameter falling within a range disclosed herein.

In some embodiments, the nanoparticles have a melting temperaturefalling within a range suitable for the matrix carrier compositionsdescribed herein. In some embodiments, the nanoparticles have a meltingtemperature (Tm) of over 600° C. In some embodiments, the Tm is from 600to 4500° C., e.g., in some embodiments, the Tm is from 800 to 4500° C.In some embodiments, the Tm is any Tm falling within a range disclosedherein. Tm may be determined using techniques well known for definingmelting temperatures for metals or nanoparticles.

Second Solid Phase—Biopolymer(s)

According to some embodiments the second phase of the matrix carrier,may include one or more biopolymers.

According to some embodiments, the biopolymers used in methods andcompositions of the present invention may include any biopolymer knownin the art. For example, the biopolymer may include a linear polymer, abranched polymer, an unbranched polymer, a cyclic biopolymer, and thelike. The Biopolymer may be naturally-occurring, hemi-synthetic, orsynthetic biopolymer. In some embodiments, the biopolymer may include amonomer, a dimmer, an oligomer and/or a polymer. In some exemplaryembodiments, the biopolymer includes a saccharide (a carbohydrate). Insome exemplary embodiments, the biopolymer includes a polysaccharide.

In some embodiments, the “Second solid phase” comprises both hydrophilicand hydrophobic residues/parts/regions. In some embodiments, thehydrophilic and hydrophobic residues interact with the hydrophobicand/or hydrophilic regions, respectively, of the pharmaceutical agentand/or components of the “Second solid phase” and/or the nanoparticle(of the “First solid phase”).

In some embodiments, one biopolymer is used. In other embodiments, morethan one biopolymer is used. In some embodiments, the biopolymer islinear in structure. In some embodiments, the biopolymer is cyclic instructure. In some embodiments, the biopolymer is branched in structure.

In some embodiments, the “Second solid phase” has a melting temperature(Tm) under 400° C. In some embodiments, the Tm is below 350° C. In someembodiments, the Tm is below 300° C. In some embodiments, the Tm isbelow 250° C. In some embodiments, the Tm is below 200° C. In someembodiments, the Tm is below 150° C. In some embodiments, the Tm is from100 to 400° C. In some embodiments, the Tm is any Tm falling within arange disclosed herein. Tm may be determined using standard techniquesknown in the art for analyzing the melting temperatures of polymers.

In some embodiments, the biopolymer is a saccharide. The saccharide is,in some embodiments, a naturally-occurring saccharide. In someembodiments, the saccharide is a synthetic saccharide.

In some embodiments, the biopolymer comprises a polysaccharide.Biopolymers such as polysaccharides have been known in the art asexcipients in oral dosage forms, as disclosed, for example in U.S. Pat.No. 6,667,060 and US patent application 2004/0115264. The polysaccharidecomprises, in some embodiments, a naturally-occurring polysaccharide. Insome embodiments, the polysaccharide comprises a syntheticpolysaccharide. Non limiting examples of synthetic polysaccharides canbe found in U.S. Pat. No. 6,528,497 and in Okada M. et al. Polymerjournal, 15 (11); 821-26 (1983). In some embodiments, the polysaccharidecan be hemi-synthetic. In some embodiments, the biopolymer comprises atleast one positively charged polysaccharide. But, whether thepolysaccharide is naturally-occurring, hemi-synthetic, or synthetic, itis a biopolymer as that term is used herein.

In some embodiments, the polysaccharide comprises a branchedpolysaccharide. This term is well understood to those skilled in the artand can refer to any number and structure of branches in thepolysaccharide. In some embodiments, the polysaccharide comprises anaturally-occurring branched polysaccharide. In some embodiments, thepolysaccharide comprises a synthetic branched polysaccharide.

In some embodiments, the biopolymer of the Second solid phase mayinclude an unbranched biopolymer. “Unbranched biopolymer” refers tolinear or cyclic biopolymers. Non limiting examples of unbranchedbiopolymers include, for example, but not limited to glucosaminoglycans(GAGs) or mucopolysaccharides, which are long unbranched polysaccharidesconsisting of a repeating disaccharide unit, cyclodextrin, and the like.

In some embodiments, the biopolymer of the Second solid phase mayinclude a carbohydrate selected from nutriose, maltsorb, xylitol,mannitol, rice polysaccharide, starch, dextrin, cellulose, chitin, alphaglucan, beta glucan, amylopectin, glycogen, chitosan, glucosaminoglycans(GAGs), mucopolysaccharides and derivatives thereof.

In some embodiments, the biopolymer of the Second solid phase mayinclude polysaccharide comprising starch. Non-limiting examples ofstarch are corn starch, potato starch, rice starch, wheat starch, purumstarch, and starch from algae. In some embodiments, the starch is anyother starch known in the art.

In some embodiments, the biopolymer of the Second solid phase mayinclude a polysaccharide comprising a dextrin. “Dextrin” in anotherembodiment refers to a low-molecular-weight carbohydrate produced by thehydrolysis of starch. In another embodiment, the term refers to a linearα-(1,4)-linked D-glucose polymer starting with an α-(1,6) bond or amixture of same. Dextrins are widely commercially available and can beproduced inter alia by digestion of branched amylopectin or glycogenwith α-amylase. A non-limiting example of a dextrin is a maltodextrinhaving the structure below. In another embodiment, the dextrin is anyother dextrin known in the art. Each possibility represents a separateembodiment of the present invention.

In some embodiments, the biopolymer of the Second solid phase mayinclude a polysaccharide comprising cellulose. A non-limiting example ofcellulose is α-cellulose. In other embodiments, the cellulose is anyother cellulose known in the art.

In some embodiments, the biopolymer of the Second solid phase mayinclude a polysaccharide comprising chitin. A non-limiting example ofchitin has the molecular formula (C₈H₁₃NO₅)n. In other embodiments, thechitin is any other chitin known in the art.

In some embodiments, the biopolymer of the Second solid phase mayinclude a polysaccharide comprising an alpha-glucan. Alpha-glucans maybe linear or branched polymers of glucose with alpha 1-2, alpha 1-3,alpha 1-4, and/or alpha 1-6 glycosidic linkages. For example,alpha-glucans such as alpha-amylose derived from plants are unbranchedlinear glucose polymers with alpha 1-4 glycosidic linkages andalpha-glucans, such as amylopectin, are derived from plants and arebranched glucose polymers with alpha 1-4 glycosidic linkages in thebackbone and alpha 1-6 linkages at branch points. In other embodiments,the alpha-glucan is any other alpha-glucan known in the art.

In some embodiments, the biopolymer of the Second solid phase mayinclude polysaccharide that is a beta-glucan. “Beta-glucan” refers tothose polysaccharides which comprise D-glucopyranosyl units which arelinked together by (1→3) or (1→4) beta-linkages. Beta-Glucans occurnaturally in many cereal grains such as oats and barley and in fungus(mushrooms) and were suggested, in clinical and animal studies toincrease certain aspects of the immune system. In addition, studiessuggest that mushroom polysaccharides may also be able to increasedendritic cell function. The molecular weight of beta-glucan moleculesoccurring in cereals is typically 200 to 2000 kDa. Non limiting exampleof beta glucan is Lentinan, which is isolated from the shiitakemushroom. In another embodiment, the beta-glucan is any otherbeta-glucan known in the art. Each possibility represents a separateembodiment of the present invention. Additional examples of thebeta-glucan is 346210 β-Glucan, isolated from Saccharomyces cerevisiae(Calbiochem production, 9008-22-4 Ref. in Merck chemicals catalogue).

In some embodiments, the biopolymer of the Second solid phase mayinclude a polysaccharide that is a glycosaminglycan (GAG) ormucopolysaccharide, which are long unbranched polysaccharides consistingof a repeating disaccharide unit. The repeating unit may include ahexose (six-carbon sugar) or a hexuronic acid, linked to a hexosamine(six-carbon sugar containing nitrogen). Some GAG chains may becovalently linked to a protein to form proteoglycans; the exception isthe GAG hyaluronan, which is uniquely synthesized without a protein coreand is “spun out” by enzymes at the cell surface directly into theextracellular space. Some examples of glycosaminoglycan uses in natureinclude heparin as an anticoagulant, hyaluronan as a component in thesynovial fluid lubricant in body joints, and chondroitins which can befound in connective tissues, cartilage and tendons. Members of theglycosaminoglycan family vary in the type of hexosamine, hexose orhexuronic acid unit they contain (e.g. glucuronic acid, iduronic acid,galactose, galactosamine, glucosamine. They may also vary in thegeometry of the glycosidic linkage. Exemplary GAG include such GAGs as,but not limited to: 385908 Hyaluronic Acid, Sodium Salt, Streptococcussp., Natural high-viscosity mucopolysaccharide with alternatingβ1,3-glucuronidic and β1,4-glucosaminidic bonds. Principalglycosaminoglycan in connective tissue fluids, Lyophized powder, (CAS9067-32-7, Calbiochem), Mushroom polysaccharides (pharma grade), suchas, for example moss, cordyceps, and the like.

In some embodiments, the at least one nanoparticle (“First Solid Phase”)and the at least one biopolymer (“Second solid phase”), that areintermolecular associated, are particulate matter.

In some embodiments, the “Second solid phase” may include a biopolymercomprising a fibrous biopolymer, for example, a dietary fiber.Biopolymers can be either naturally fibrous or made fibrous by physicaland chemical treatment. In some embodiments, the dietary fiber comprisesa water insoluble fiber. In some embodiments, the dietary fibercomprises a linear insoluble fiber. In some embodiments, the dietaryfiber comprises a water soluble fiber. In some embodiments, the dietaryfiber comprises a linear soluble fiber.

In some embodiments, the “Second solid phase” may include a biopolymercomprising a mucopolysaccharide (such as, for example, certificatedmedical mushroom mucopolysaccharides by Aloha Medicinals Inc).

In some embodiments, the “Second solid phase” may include a biopolymercomprising a structural protein.

In some embodiments, the “Second solid phase” may include a biopolymerthat can comprise either one or a plurality of types of biopolymers. Insome embodiments, the biopolymer comprises two or more types ofbiopolymers. In some embodiments, the biopolymer comprises three or moretypes of biopolymers. In some embodiments, the biopolymer comprises fouror more types of biopolymers. In some embodiments, the biopolymercomprises more than four types of biopolymers.

In some embodiments, the “Second solid phase” may include a biopolymercomprising a branched biopolymer and/or a linear biopolymer and/orcyclic biopolymer. In some embodiments, the “Second solid phase”includes a biopolymer that comprises a branched carbohydrate and alinear carbohydrate and or cyclic carbohydrate. In some embodiments, the“Second solid phase” includes biopolymer that comprise a branchedcarbohydrate and a linear carbohydrate and/or cyclic carbohydrate and/orany combination thereof. Each possibility represents a separateembodiment of the present invention.

In some embodiments, the “Second solid phase” may include a biopolymercomprising a branched biopolymer and a cyclic biopolymer. In someembodiments, the biopolymer comprises a branched polysaccharide and acyclic polysaccharide. In some embodiments, the cyclic polysaccharidecomprises a cyclodextrin. In some embodiments, the cyclodextrin isselected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin andderivatives thereof. A non-limiting example of such a combination isstarch based polysaccharide such as, but not limited to: amylopectin,and/or nutriose and/or cyclodextrin, such as, for example,beta-Cyclodextrin.

In some embodiments, the “Second solid phase” biopolymer comprises abranched biopolymer and a high molecular weight structural protein. Insome embodiments, the biopolymer comprises a branched polysaccharide anda high molecular weight structural protein.

In some embodiments, the “Second solid phase” biopolymer comprises alinear biopolymer and a cyclic biopolymer. In some embodiments, thebiopolymer comprises a linear polysaccharide and a cyclicpolysaccharide. In some embodiments, the linear polysaccharide isselected from fiber, chitin, glucans and cellulose.

In some embodiments, the “Second solid phase” biopolymer comprises abranched biopolymer, a cyclic biopolymer, and a linear biopolymer. Insome embodiments, the “Second solid phase” biopolymer comprises abranched polysaccharide, a cyclic polysaccharide, and a linearpolysaccharide. In some embodiments, the cyclic polysaccharide comprisesa cyclodextrin. In some embodiments, the linear polysaccharide isselected from chitin, glucans, fiber, maltsorb and cellulose.

In some embodiments, the “Second solid phase” biopolymer comprises abranched biopolymer, a cyclic biopolymer, and a structural protein. Insome embodiments, the “Second solid phase” biopolymer comprises abranched polysaccharide, a cyclic polysaccharide, and a structuralprotein. In some embodiments, the branched polysaccharide comprisesamylopectin. In some embodiments, the cyclic polysaccharide is acyclodextrin, e.g., α-Cyclodextrin. In some embodiments, the structuralprotein is selected from melanin and keratin, wherein in someembodiments, the keratin is in a neutral-basic (keratin 1-8) or inacidic (keratin 9-20) forms.

In some embodiments, the “Second solid phase” biopolymer comprises abranched biopolymer, a structural protein, and an insoluble fiber. Insome embodiments, the “Second solid phase” biopolymer comprises abranched polysaccharide, a structural protein, and an insoluble fiber.In some embodiments, the branched polysaccharide is amylopectin. In someembodiments, the structural protein is keratin.

In some embodiments, the “Second solid phase” biopolymer comprises abranched biopolymer, a linear biopolymer, and an insoluble fiber. Insome embodiments, the “Second solid phase” biopolymer comprises abranched polysaccharide, a linear polysaccharide, and an insolublefiber. In some embodiments, the branched polysaccharide is amylopectin.In some embodiments, the linear polysaccharide is chitin.

In some embodiments, and without wishing to be bound to theory ormechanism, the use of a chosen “Second solid phase” biopolymer (or anycombination of biopolymers), may offer an added value to the matrixcarrier composition, which may be dictated by the intrinsic propertiesof the biopolymer. For example, the biopolymer may be used to target thematrix carrier composition to a target area and/or to allow the accessof the matrix carrier to a required location. For example, mannitol,which is known to cross the blood-brain barrier (BBB) may be used in thematrix composition, to assist the carrier in crossing that barrier. Forexample, the biopolymer may have intrinsic beneficial activity that mayaugment or enhance the beneficial activity of the reagent in thecarrier. For example, beta glucan, such as, Lentinan, is known to havebeneficial effect on the immune system.

According to some embodiments, “Second solid phase” biopolymer may be astructural protein. As used herein, “structural protein” refers to aprotein, which may be a biopolymer, and is included for the structure itconfers to the particulate matter. In some embodiments, the term refersto a protein, which may be a biopolymer, that confers structure to acell, cellular membrane, or extracellular membrane in vivo. In someembodiments, the structural protein lacks therapeutic, pharmacologic,pharmaceutical, and/or biological activity whereas in other embodimentsthe structural protein has an additional therapeutic activity. Inembodiments wherein the structural protein has therapeutic activity, thepharmaceutical agent, in some embodiments, is different from thestructural protein.

In some embodiments, the structural protein comprises both hydrophilicand hydrophobic residues. In some embodiments, those residues interactwith the hydrophobic and/or hydrophilic regions, respectively, of thepharmaceutical agent and/or the “Second solid phase” biopolymer and/orthe “First solid phase” nanoparticle.

In some embodiments, the structural protein comprises a high molecularweight (MW) structural protein. In some embodiments, the mean MW of thestructural protein is at least 100 kilodalton (kDa). In someembodiments, the mean MW is at least 150 kDa. In some embodiments, themean MW is at least 200 kDa. In some embodiments, the mean MW is atleast 300 kDa. In some embodiments, the mean MW is at least 400 kDa. Insome embodiments, the mean MW is at least 500 kDa. In some embodiments,the mean MW is at least 600 kDa. In some embodiments, the mean MW is atleast 800 kDa. In some embodiments, the mean MW is at least 1000 kDa. Insome embodiments, the mean MW is from 100 to 1000 kDa. In someembodiments, the mean MW is from 150 to 1000 kDa. In some embodiments,the mean MW is from 200 to 1000 kDa. In some embodiments, the mean MW isfrom 100 to 800 kDa. In some embodiments, the mean MW is from 100 to 600kDa.

In some embodiments, the structural protein has a Tm under 400° C. Tmmay be determined using standard techniques known in the art foranalyzing the melting temperatures of proteins.

In some embodiments, the structural protein comprises a fibrous protein.In some embodiments, the structural protein comprises a scleroprotein.In some embodiments, the structural protein is selected from elastin,collagen, keratin, and fibrinogen. In some embodiments, the structuralprotein is any other fibrous protein or scleroprotein known in the art.

In some embodiments, the structural protein comprises elastin.Non-limiting examples of elastin proteins are described, for example, inGenBank Accession numbers NP_031951, NP_786966, and AAC98394. In someembodiments, the elastin is any other elastin known in the art.

In some embodiments, the structural protein comprises collagen.Non-limiting examples of collagen proteins include those encoded by genesymbols COL3A1, COL14A1, COL11A2, COL5A2, COL11A1, COL5A1, COL4A6,COL4A5, COL4A4, COL4A3, COL4A2, COL1A2, COL5A3, COL18A1, COL12A1,COL19A1, COL24A1, COL4A1, and COL2A1. In some embodiments, the collagenis any other collagen known in the art.

In some embodiments, the structural protein comprises keratin.Non-limiting examples of keratin proteins include keratin 18, keratin14, keratin 3, and keratin 86 (GenBank Accession numbers P05783, P02533,P12035, 043790, respectively. In some embodiments, the keratin is anyother keratin known in the art.

In some embodiments, the structural protein comprises fibrinogen.Fibrinogen is a glycoprotein composed of three pairs of polypeptides:two alpha, two beta, and two gamma chains. Non-limiting examples of thefibrinogen alpha, beta, and gamma chains are described, inter alia, inGenBank Accession numbers P02671, P02675, and P02679. In someembodiments, the fibrinogen is any other fibrinogen known in the art.

Oil

The oil may be composed of either one or a plurality of types of oils.In some embodiments, the oil comprises a plurality of oils. In someembodiments, the matrix carrier composition described herein comprisesthree or more oils. In some embodiments, the matrix carrier compositiondescribed herein comprises four or more oils. In some embodiments, thematrix carrier composition described herein comprises more than fouroils.

In some embodiments, the at least one oil is liquid. In someembodiments, the at least one oil is selected from solid and liquidoils. In some embodiments, the at least one oil is selected from solidoils.

According to some embodiments, the component has a melting temperature(Tm) of at least 5° C. In some embodiments, the oil comprises acomponent having a relatively high melting temperature. In someembodiments, the high Tm component is a liquid at room temperature. Insome embodiments, the oil is the high Tm component. In some embodiments,the high-Tm component is included in addition to another oil. Anon-limiting example of a high-Tm oil is jojoba oil. In someembodiments, the high Tm oil is any other high melting temperature oilknown in the art. In some embodiments, the high Tm oil is used as themajority of the oil. Tm may be determined using standard techniquesknown in the art for analyzing the melting temperatures of proteins.

In some embodiments, the oil comprises at least one lipid. In someembodiments, the oil comprises at least one naturally-occurring lipid.

In some embodiments, the oil comprises one or more naturally-occurringoils. In some embodiments, the oil comprises a mixture of naturalvegetable oils. In some embodiments, the oil comprises one or more oilsselected from natural vegetable oils and synthetic analogues thereof.

In some embodiments, the mainly non-polar oil may include polarfractions/parts/regions.

In some embodiments, the oil comprises sesame oil. In some embodiments,the oil comprises olive oil. In some embodiments, the oil compriseslinseed oil. In some embodiments, the oil comprises evening primroseoil.

In some embodiments, the oil comprises sea buckthorn oil. In someembodiments, the oil is selected from sesame oil, olive oil, linseedoil, palm oil, jojoba oil, silicon oil and sea buckthorn oil. In someembodiments, the oil is selected from sunflower oil, corn oil, soybeanoil, jojoba oil, marrow oil, grapeseed oil, hazelnut oil, apricot oil,macadamia oil, palm oil, almond oil, castor oil, and the like, or anycombination thereof.

In some embodiments, the oil may be of animal origin, such as, forexample, lanolin.

In some embodiments, the oil comprises synthetic oil, for examplesilicone oil with molecular weight providing optimal viscosity.

In some embodiments, the oil comprises at least one naturally-occurringoil and at least one synthetic oil.

In some embodiments, the oil comprises unsaturated and saturated oils inthe ratio providing optimal viscosity.

In some embodiments, the oil comprises a fatty alcohol. In someembodiments, the oil comprises 2-octyldodecanol. In some embodiments,the oil is selected from a fatty acid ester and a phenylsilicone. Insome embodiments, the oil is selected from phenyltrimethicones,diphenyldimethicones, and poly-methylphenylsiloxanes.

In some embodiments, an oil component comprises a component capable ofstimulating secretion of bile salts or bile acids when ingested by asubject. In some embodiments, the bile-stimulating component is an oil.In some embodiments, the component comprises olive oil or an extractthereof. In some embodiments, the component is any other bile salt/acidstimulating lipid-soluble substance known in the art. In someembodiments, the oil is the bile salt/acid stimulating substance. Insome embodiments, the bile salt/acid stimulating substance is asubstance separate from the oil.

In some embodiments, the oil may contain at least one anti-oxidant. Forexample, sea buckthorn (oblepicha) oil contains beta-carotene. In someembodiments, any other oil enriched in at least one anti-oxidant may beused. In some embodiments, any other oil enriched in at least onevitamin may be used. Non-limiting examples are Vitamin A, Vitamin E,beta-carotene, Vitamin D or any combination thereof.

In some embodiments, the oil may be another suitable oil known in theart.

In some embodiments, the matrix carrier composition comprises anadditional oil component. The additional oil component may comprise anadditional oil or mixture of oils. In some embodiments, the oil of theadditional oil component is olive oil. In some embodiments, the oil isanother suitable oil known in the art.

In some embodiments, the additional oil component further comprises anantioxidant.

In some embodiments, the additional oil, or mixture of oils may have ahigher viscosity than the first-added oil or mixture of oils.

In some embodiments, the matrix carrier composition further comprises athird oil or mixture of oils in addition to the above-describedadditional oil component. In some embodiments, the third oil componentcomprises an antioxidant.

In some embodiments, the third oil component comprises sesame oil. Insome embodiments, the third oil component is another suitable oil knownin the art.

In some embodiments, the third oil, oil or mixture of oils may have ahigher viscosity than the additional oil or mixture of oils. Notlimiting example for a third oil is a palm oil.

In some embodiments, the at least one oil comprises at least one wax. Insome embodiments, the wax is a substance having the followingproperties: (a) plastic (malleable) at normal ambient temperature; (b)having a melting point above approximately 45° C. (113° F.); (c) a lowviscosity when melted, relative to a typical plastics; (d) insoluble inwater; and (e) hydrophobic. In some embodiments, the wax is a naturalwax, for example bees wax, a wax derived from plant material, or asynthetic wax prepared by esterification of a fatty acid and a longchain alcohol. Other suitable waxes include petroleum waxes such as aparaffin wax.

Use of the Matrix Carrier Composition

The matrix carrier compositions described herein may be combined withone or more pharmaceutical agents, as described below, to produce apharmaceutical composition/delivery system, suitable for administration.Administration may include any type of administration, such as, forexample, oral administration, parenteral administration, topicaladministration, and the like.

In some embodiments, oral administration of the pharmaceuticalcompositions described herein results in enhanced potency of thepharmaceutical agent as compared to oral administration of thepharmaceutical agent alone. In some embodiments, oral administration ofthe pharmaceutical compositions described herein results in at leastcomparable, if not enhanced, potency of the pharmaceutical agent ascompared to non-oral administration of the pharmaceutical agent. In someembodiments, oral administration of the pharmaceutical compositiondescribed herein provides an increase in potency by, for example,extending the pharmaceutical agent's life time in blood, improving thepharmaceutical agent's targeting ability, and/or decreasing thepharmaceutical agent's side effects, as compared to the drug when orallyadministered alone.

In some embodiments, the relative potency of the pharmaceutical agentwhen administered orally as part of the pharmaceutical compositionsdescribed herein is at least 20% higher than the relative potency of thepharmaceutical agent when orally administered alone; alternatively, atleast 50% higher; alternatively, at least 2 times higher; alternatively,at least 3 times higher; alternatively at least 4 times higher;alternatively, at least 5 times higher; alternatively, at least 10 timeshigher; alternatively, more than 10 times higher.

In some embodiments, the ADME profile of the pharmaceutical agent whenadministered orally as part of the pharmaceutical compositions describedherein is altered as compared to the ADME profile of the pharmaceuticalagent when orally administered alone.

In some embodiments, the oral administration of the pharmaceuticalcompositions described herein results in enhanced oral bioavailabilityof the pharmaceutical agent as compared to oral administration of thepharmaceutical agent alone. In some embodiments, the relative oralbioavailability of the pharmaceutical agent when administered as part ofthe pharmaceutical compositions described herein is at least 10% higherthan the relative oral bioavailability of the pharmaceutical agent whenorally administered alone; alternatively, at least 20% higher;alternatively, at least 50% higher; alternatively, at least 60% higher;alternatively, at least 70% higher; alternatively, at least 80% higher.In some embodiments, the relative oral bioavailability of thepharmaceutical agent when administered as part of the pharmaceuticalcompositions described herein is at least two times higher than therelative oral bioavailability of the pharmaceutical agent when orallyadministered alone; alternatively, at least three times higher;alternatively at least four times higher; alternatively, at least fivetimes higher; alternatively, at least ten times higher; alternatively,more than ten times higher.

In some embodiments, oral administration of the pharmaceuticalcomposition described herein may result in improved targeting and/orspecificity of the pharmaceutical agent as compared to oraladministration of the active ingredient alone. Such targeting andspecificity, in some embodiments, may be further improved through theuse of one or more enhancers, as discussed herein, as part of thepharmaceutical composition described herein.

In some embodiments, the oral administration of the pharmaceuticalcompositions described herein results in increased half life in plasmaor the lymph circulation of the pharmaceutical agent as compared withoral administration alone. It is to be understood, that the ability toincrease the half-life of the pharmaceutical agent by using thepharmaceutical compositions described herein may be independent of thepharmaceutical agent's oral bioavailability. The pharmaceuticalcompositions described herein, when administered orally, may be used toincrease half-life of poorly as well as highly orally bioavailabledrugs. In some embodiments, the half-life of the pharmaceutical agent inthe pharmaceutical compositions described herein, when administeredorally, is at least 10% higher than the half-life of the pharmaceuticalagent when orally administered alone; alternatively, at least 20%higher; alternatively at least 30% higher; alternatively, at least 40%higher; alternatively, at least 50% higher; alternatively, at least 60%higher; alternatively, at least 70% higher; alternatively, at least 80%higher; alternatively, at least 90% higher; alternatively, at least 2times higher; alternatively at least 3 times higher.

In some embodiments, oral administration of the pharmaceuticalcomposition described herein may result in a more controlled lifetime ofthe pharmaceutical agent in the blood and lymph circulation as comparedto administration of the pharmaceutical agent by injection orinhalation.

In some embodiments, oral administration of the pharmaceuticalcomposition described herein may not result in a high initialconcentration peak upon administration as compared with that found frominjected or inhaled formulations of the same pharmaceutical agent. Suchhigh concentration may lead to side effects such as immune response andinflammation process, similar to hematoma.

In some embodiments, oral administration of the pharmaceuticalcomposition described herein may result in a slower release profile ofthe active reagent in the blood as compared to oral administration ofthe active ingredient alone.

In some embodiments, oral administration of the pharmaceuticalcomposition described herein may result in decreased side effects orallergic reactions, even when administered orally at order of magnitudehigher daily doses, as compared to oral administration of thepharmaceutical agent alone. Such decrease may be in the number ofpatients reporting the side effects or allergic reactions or in theseverity of the side effects or allergic reactions.

In some embodiments, oral administration of the pharmaceuticalcomposition described herein may result in the ability to treat diseasesand conditions that otherwise would not be treatable with the samepharmaceutical agent when orally administered alone. In someembodiments, oral administration of the pharmaceutical compositiondescribed herein may result in an improved ability to treat diseases andconditions than when the pharmaceutical agent is administered alone in away other than orally, such as by intravenous or inhalationadministration.

In some embodiments, oral administration of the pharmaceuticalcomposition described herein may result in the use of a lower dose(amount) of the pharmaceutical agent to achieve a certain effect ascompared to the dose (amount) of pharmaceutical agent required toachieve that same effect when administered orally alone or whenadministered alone by a way other than orally.

In some embodiments, oral administration of the pharmaceuticalcomposition described herein may result in different biodistribution,(that is, the distribution in various tissues and organs) as compared tothe biodistribution of the pharmaceutical agent when administered orallyalone or when administered alone by parenteral route.

Provided is a pharmaceutical composition comprising an intermolecularassociation of at least one pharmaceutical agent, at least onebiopolymer, nanoparticles, and at least one oil.

In some embodiments, the pharmaceutical composition is anhydrous. Insome embodiments, the composition is preferably in the absence of waterand surfactants.

In some embodiments, the pharmaceutical composition is formulated in aform suitable for oral delivery using conventional methods known in theart. In some embodiments, the form is selected from capsules (includingsoft gel capsules, hard gelatin capsules), tablets (including coatedtablets, pressured tablets), liquid form (including solutions andsuspensions), jell form, liquid form coated by jell or hard phase,pastes, and the like, or any combination thereof. In some embodiments,the pharmaceutical composition may be formulated in the form of small ormicro-droplets impregnated into biocompatible soluble porous nutritionalmaterial like agar, fruit jelly, cornflex, etc or into any biocompatiblewater based gel.

In some embodiments, parenteral administration of the pharmaceuticalcompositions described herein may be used. The parenteral administrationmay be used in patients with any gastrointestinal problem, swallowingdifficulties or in accordance with the patient preference or medicaldecision. The parenteral use of the pharmaceutical agent with thepharmaceutical compositions described herein, may result in differentpharmacodynamic and/or pharmacokinetics profile, as compared to theparenteral administration of the pharmaceutical agents without thematrix carrier of the invention.

Pharmaceutical Agent

In some embodiments, the matrix carrier compositions described hereinmay be combined with one or more pharmaceutical agents. In someembodiments, the one or more pharmaceutical agents may exhibit anon-covalent interaction with the matrix carrier composition, or one ormore components thereof. In some embodiments, the one or morepharmaceutical agents is covalently bonded to one or more of thecomponents of the matrix carrier composition.

In some embodiments, the pharmaceutical agent comprises one or morecompounds with poor oral bioavailability. In some embodiments, thepharmaceutical agent is poorly absorbed or not absorbed at all from thegastrointestinal tract or gut. In some embodiments, the pharmaceuticalagent has poor water solubility and/or slow dissolution rate.

In some embodiments, the pharmaceutical agent is a drug agent, which hasa short half life (t½) in plasma. In some embodiments, thepharmaceutical agent is a drug with plasma half-life shorter than 10hours; alternatively, a drug with plasma half-life shorter than 8 hours;alternatively, a drug with plasma half-life shorter than six hours;alternatively, a drug with plasma half-life shorter than four hours;alternatively, a drug with plasma half-life shorter than three hours;alternatively, a drug with plasma half-life shorter than two hours.

In some embodiments, the one or more pharmaceutical agents are poorlywater-soluble and in a crystalline, semi-crystalline, amorphous state,or combination of such states.

In some embodiments, the pharmaceutical agent is branched in structure.

In some embodiments, the pharmaceutical agent is substantiallyhydrophobic.

In some embodiments, the pharmaceutical agent is substantiallyhydrophilic.

In some embodiments, the one or more pharmaceutical agents arewater-soluble.

In some embodiments, the pharmaceutical composition comprises more thanone pharmaceutical agent.

In some embodiments, the pharmaceutical agent may include a nutritionalagent or a combination of nutritional agents. The term “pharmaceuticaldrug” is intended to include substances having pharmacological and/orpharmaceutical, and/or biological activity.

Additional Components

According to some embodiments, the matrix carrier composition mayfurther include one or more additional components that may be used toenhance the effect achieved by the use of the matrix carrier compositionand provide an added value to the matrix. In embodiments wherein the oneor more additional components is an enhancer, as discussed below, thatenhancer may be associated with the matrix carrier composition. Forexample, the additional component(s) may have structural effect,beneficial therapeutic effect (that may be synergistic to the activereagent of the matrix), targeting effect, allow better control of thepharmacokinetics of the compositions, and the like, or any combinationthereof. The additional components may include any type of naturaloccurring molecules, synthetic molecules, or combinations thereof. Forexample, various amino acids (such as, for example, but not limited toArginine, Histamine, Aspartate, Glutamate, and the like), may be used inthe composition, as a targeting enhancer. For example, moleculesisolated from natural sources may be used in order to provide addedtherapeutic value to the active reagent in the matrix. For example, theadditional components may include extracts of various natural sources.Natural sources may include, for example, mushrooms, such as, forexample, medicinal mushrooms, cordiceps mushrooms, plants, animals andthe like. Exemplary molecules isolated from mushrooms may include suchcomponents as, but not limited to: polysaccharides, such as, forexample, beta-glucans which stimulate the innate branch of the immunesystem. beta-glucans have been shown to have the ability to stimulatemacrophage, NK cells, T cells and the production of immune systemcytokines; antioxidants such as, for example, but not limited toascorbic acid, tocopherols, phenolic compounds, and carotenoids;alpha-glucosidase inhibitor, which have a beneficial effect on bloodsugar levels; anticholesterol compounds, such as, for example,eritadenine, lovastatin, and the like; molecules having anti hormoneactivity; vitamin D2; Molecules having antiviral, antibacterial, and/orantifungal properties; molecules having anti-cancer effect, such as, forexample, polysaccharide compounds isolated from maitake mushroom.Molecules isolated from plants may include such molecules as, but notlimited to polyphenols, which are characterized by the presence of morethan one phenol unit or building block per molecule. Polyphenols aregenerally divided into hydrolyzable tannins (gallic acid esters ofglucose and other sugars) and phenylpropanoids, such as lignins,flavonoids, and condensed tannins and may have antioxidant activity. Insome embodiments, the additional component may include an isolatedmolecule, an isolated fraction or an extract of a cordiceps molecule. Insome embodiments, the additional component may include any type ofGlucagon like peptide (GLP), such as, GLP-1, GLP-2, or analogs thereof.Glucagon-like peptide is derived from the transcription product of theproglucagon gene. The major source of GLP in the body is the intestinalL cell that secretes GLP as a gut hormone. GLP-1 secretion by L cells isdependent on the presence of nutrients in the lumen of the smallintestine. Physiological roles of GLP include: increasing insulinsecretion from the pancreas in a glucose-dependent manner; decreasingglucagon secretion from the pancreas; increasing beta cells mass andinsulin gene expression; inhibiting acid secretion and gastric emptyingin the stomach; decreasing food intake; promoting insulin sensitivity.In some embodiments and without wishing to be bound to mechanism ortheory, the GLP in the matrix provides a structural effect bystabilizing the matrix structure. In addition, the GLP provides an addedbeneficial effect (for example, when used in a matrix carriercomposition which includes insulin as a protein reagent) by providingadditional means of controlling blood sugar level, and by preventingulcer. Furthermore, the use of GLP in the matrix carrier composition mayaid in targeting the matrix carrier.

In some embodiments, the matrix carrier composition and/or thepharmaceutical composition further comprises at least one antioxidant.In some embodiments, the at least one antioxidant may include, but notlimited to vitamin E, superoxide dismutase (SOD), catalase, glutationperoxidase, N-acetylcysteine, Vitamin A, Vitamin D, Vitamin C, omega-3,and beta-carotene.

In some embodiments, substantially anhydrous matrix carrierpharmaceutical composition may include molecules and/or particles havinghydrophilic properties. Non limiting examples are hydrophilic silica,water soluble vitamins, and the like.

In some embodiments, the matrix carrier composition and/or thepharmaceutical composition further comprises at least onepharmaceutical-grade surfactant. Surfactants are well known in the art,and are described, inter alia, in the Handbook of PharmaceuticalExcipients (eds. Raymond C Rowe, Paul J Sheskey, and Sian C Owen,copyright Pharmaceutical Press, 2005). In some embodiments, the at leastone surfactant is any other surfactant known in the art. Emulsifiers andemulgators, each being examples of surfactants, are well known in theart, and are described, inter alia, in the Handbook of PharmaceuticalExcipients (ibid). Non-limiting examples of emulsifiers and emulgatorsare eumulgin, Eumulgin B1 PH, Eumulgin B2 PH, hydrogenated castor oilcetostearyl alcohol, and cetyl alcohol. In some embodiments, theemulsifier or emulgator is any other emulsifier or emulgator known inthe art.

In some embodiments, the matrix carrier composition and/or thepharmaceutical composition further comprises at least onepharmaceutical-grade stabilizer. Stabilizers are well known in the art,and are described, inter alia, in the Handbook of PharmaceuticalExcipients (ibid). In some embodiments, the at least one stabilizer isany other stabilizer known in the art.

According to some embodiments, the matrix carrier composition and/orpharmaceutical composition may further include an enhancer and/ortargeting component.

The term “Enhancer” refers to any substance that directly ornon-directly enhances biological and/or pharmacological potency of thepharmaceutical agent. Non limiting examples of enhancers include, butnot limited to: omega-3, beta-caroten, bioflavanoid, biotin,antioxidant, amino acid, SOD, catalase, salts of microelements, and thelike, or any combination thereof. For example, beta glucan, such as,Lentinan, is known to have beneficial effect on the immune system andmay be used as enhancer.

The term “Targeting component”—refers to any substance that can improvetargeting and/or bio-distribution of the pharmaceutical agent to adesired spatial location. The targeting component may include anytargeting agent known in the art, that may be used to target thepharmaceutical agent to the desired spatial location. For example, thetargeting component may include such components as, but not limited to:Specific antibodies; Specific polysaccharides; Positively and/ornegatively charged amino acids and/or polysaccharides; Small moleculeswhich have increased affinity to specific receptors on the tumor cellmembrane and/or organelle; Short peptides; antagonist receptor, and thelike, or any combination thereof. In some embodiments, the targetingenhancer is chosen from positively charged amino acids, such as lysine,arginine, histidine, aspartate and glutamate. In some embodiments, theenhancer is a sugar alcohol. In some embodiments, the targetingcomponent is selected from mannitol and xylitol. Non limiting examplesof targeting agents include, but not limited to: mannitol (that mayimprove blood brain barrier penetration), amino acid, antibodies, andthe like, or any combination thereof.

In some embodiments, metals, metalloproteins, electrolytes, or anycombination thereof, may be used as targeting enhancers to aid intargeting the pharmaceutical agents to a desired spatial location, basedon local environment, in that location. The targeting enhancers may beadded at different steps of production, depending on their propertiesand the desired action. The local environment may include suchparameters as, but not limited to: local acidity, local temperature,local concentration of the pharmaceutical agent, membrane potentialdistribution, or any combination thereof.

In some embodiments, the enhancer is selected from: bioflavanoids, heatshock proteins, microelements and the like.

According to some embodiments, the pharmaceutical composition mayinclude more than one pharmaceutical agent with one or more enhancersand/or targeting components, or any combination thereof. Eachpossibility represents a separate embodiment of the present invention.

In some embodiments, the matrix carrier composition and/or thepharmaceutical composition may further comprise at least one enhancer ofthe therapeutic activity of the pharmaceutical agent. In someembodiments, the matrix carrier composition and/or the pharmaceuticalcomposition further comprises at least one cofactor.

In some embodiments, as understood by those of skill in the art, anenhancer may exhibit therapeutic activity. That is, in some embodiments,an enhancer may serve a dual function, namely as a pharmaceutical agentin its own right and as an agent that enhances the activity of adifferent pharmaceutical agent.

In some embodiments, the matrix carrier composition and/or thepharmaceutical composition further comprises at least one amino acidselected from arginine, lysine, aspartate, glutamate, and histidine. Insome embodiments, analogues and modified versions of arginine, lysine,aspartate, glutamate and histidine are included in the terms “arginine,”“lysine,” “aspartate”, “glutamate” and “histidine,” respectively. Insome embodiments, the at least one amino acid promotes interaction ofthe pharmaceutical agent with a target cell.

In some embodiments, the at least one excipient provides a desired tasteto the pharmaceutical composition. In some embodiments, the at least oneexcipient influences the drug consistency, and the final dosage formsuch as a gel capsule, hard gelatin capsule, tablet or soft gel.

Non limiting examples of excipients include:

Antifoaming agents (dimethicone, simethicone);

Antimicrobial preservatives (benzalkonium chloride, benzelthoniumchloride, butylparaben, cetylpyridinium chloride, chlorobutanol,chlorocresol, cresol, ethylparaben, methylparaben, methylparaben sodium,phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuricnitrate, potassium benzoate, potassium sorbate, propylparaben,propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodiumpropionate, sorbic acid, thimerosal, thymol);

Chelating agents (edetate disodium, ethylenediaminetetraacetic acid andsalts, edetic acid);

Coating agents (sodium carboxymethyl-cellulose, cellulose acetate,cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceuticalglaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer,methylcellulose, polyethylene glycol, polyvinyl acetate phthalate,shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax,zein);

Colorants (caramel, red, yellow, black or blends, ferric oxide);

Complexing agents (ethylenediaminetetraacetic acid and salts (EDTA),edetic acid, gentisic acid ethanolmaide, oxyquinoline sulfate);

Desiccants (calcium chloride, calcium sulfate, silicon dioxide);

Emulsifying and/or solubilizing agents (acacia, cholesterol,diethanolamine (adjunct), glyceryl monostearate, lanolin alcohols,lecithin, mono- and di-glycerides, monoethanolamine (adjunct), oleicacid (adjunct), oleyl alcohol (stabilizer), poloxamer, polyoxyethylene50 stearate, polyoxyl 35 caster oil, polyoxyl 40 hydrogenated castoroil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate80, propylene glycol diacetate, propylene glycol monostearate, sodiumlauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitanmonooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid,trolamine, emulsifying wax);

Flavors and perfumes (anethole, benzaldehyde, ethyl vanillin, menthol,methyl salicylate, monosodium glutamate, orange flower oil, peppermint,peppermint oil, peppermint spirit, rose oil, stronger rose water,thymol, tolu balsam tincture, vanilla, vanilla tincture, vanillin);

Humectants (glycerin, hexylene glycol, propylene glycol, sorbitol);

Polymers (e.g., cellulose acetate, alkyl celluloses,hydroxyalkylcelluloses, acrylic polymers and copolymers);

Suspending and/or viscosity-increasing agents (acacia, agar, alginicacid, aluminum monostearate, bentonite, purified bentonite, magmabentonite, carbomer 934p, carboxymethylcellulose calcium,carboxymethylcellulose sodium, carboxymethycellulose sodium 12,carrageenan, microcrystalline and carboxymethylcellulose sodiumcellulose, dextrin, gelatin, guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesiumaluminum silicate, methyl cellulose, pectin, polyethylene oxide,polyvinyl alcohol, povidone, propylene glycol alginate, silicon dioxide,colloidal silicon dioxide, sodium alginate, tragacanth, xanthan gum);

Sweetening agents (aspartame, dextrates, dextrose, excipient dextrose,fructose, mannitol, saccharin, calcium saccharin, sodium saccharin,sorbitol, solution sorbitol, sucrose, compressible sugar, confectioner'ssugar, syrup); or any combination thereof.

This list is not meant to be exclusive, but to be merely representativeof the classes of excipients and the kinds of excipients which may beused in oral pharmaceutical compositions described herein.

Methods of Manufacturing of Matrix Carrier Compositions

According to some embodiments, there are provided methods ofmanufacturing the matrix carrier composition described herein. In someembodiments, the method, intended to illustrate the disclosure andwithout however limiting the scope thereof, comprises at least some ofthe following steps:

-   -   1. Activation of the second solid phase surface of the        matrix-carrier by additional milling, vacuum treatment, chemical        or ultra-sound cleaning or reduction.    -   2. Mixing biopolymers with liquid oils under vacuum or in inert        atmosphere.    -   3. Inserting nanoparticles into oils and optional additional        vacuum treatment for removing air from the nanoparticles surface    -   4. Inserting pharmaceutical agent(s) into pure oils, oils with        hydrophobic nanoparticles or oils with biopolymers, with or        without silica, depending on physical properties (such as        hydrophobicity) of the pharmaceutical agent.    -   5. Mixing and homogenization of the system may take into        consideration the sensitivity of the pharmaceutical agent to        mechanical stress. This process maybe performed under inert        atmosphere with control of temperature, rate and time. The        homogenization may decrease the viscosity and promote packing.

The “maturation” of the matrix carrier composition may be achieved bymaintaining under controlled temperature (for example, in the range ofabout 1-37° C.) for 1-72 hours with or without inert atmosphere.

According to some embodiments, the order of manufacturing steps maydepend on the specific equipment used and the properties of thepharmaceutical agent and may be changed accordingly.

In other embodiments, the method, intended to illustrate the disclosureand without however limiting the scope thereof, comprises:

-   -   mixing in at least one oil, nanoparticles, and at least one        biopolymer, whereby an intermolecular association of the at        least one biopolymer, the nanoparticles, and the at least one        oil is formed.

In some embodiments, the method of manufacturing the matrix carriercomposition, intended to illustrate the disclosure and without howeverlimiting the scope thereof, comprises:

-   -   a) combining nanoparticles with at least one biopolymer; and    -   b) blending the combination into at least one oil,

whereby an intermolecular association of the at least one biopolymer,the nanoparticles, and the at least one oil is formed.

In some embodiments the mixing may involve dry mixing. In embodimentsinvolving dry mixing, combining the nanoparticles with at least onebiopolymer further comprises the step of confirming that the combinationis properly homogenized. In some embodiments, any of the following threetests are utilized, it being sufficient for determining properhomogenization if a positive result is obtained in any of the threetests, even though one or more of the other tests may not produce apositive result: (a) the mixture appears homogenous; (b) the volume ofthe mixture is smaller than the sum of volumes of the two components;and (c) the mixture does not sink when placed on the surface of a stillbody of water. Should the combination fail to meet any of those threecriteria, then, in some embodiments, the method further comprises addingadditional nanoparticles or a hydrophobic agent to the mixture. Thesesteps are repeated until the combination meets at least one of the abovecriteria.

In some embodiments, the method of manufacturing the matrix carriercomposition, intended to illustrate the disclosure and without howeverlimiting the scope thereof, comprises the steps of:

-   -   a) combining nanoparticles, at least one biopolymer and at least        one structural protein; and    -   b) blending the combination into at least one oil

whereby an intermolecular association of the at least one biopolymer,the nanoparticles, the at least one structural protein, and the at leastone oil is formed.

Also provided are methods of manufacturing the pharmaceuticalcompositions described herein.

In some embodiments, the method of manufacturing the pharmaceuticalcompositions comprises the steps of:

-   -   (a) providing a matrix carrier composition;    -   (b) mixing at least one pharmaceutical agent with at least one        oil; and    -   (c) combining the matrix carrier composition with the mixture of        the pharmaceutical agent with the at least one oil.

In some embodiments, the method of manufacturing the pharmaceuticalcompositions comprises the steps of:

-   -   (a) mixing nanoparticles with at least one biopolymer;    -   (b) mixing at least one pharmaceutical agent with at least one        oil; and    -   (c) combining the mixture of nanoparticles and the at least one        biopolymer with the mixture of the pharmaceutical agent with the        at least one oil.

In some embodiments, the method of manufacturing the pharmaceuticalcompositions comprises the steps of:

-   -   (a) mixing at least one biopolymer with at least one oil;    -   (b) mixing nanoparticles with at least one oil;    -   (c) combining the mixture of nanoparticles and the at least one        biopolymer with the mixture of the pharmaceutical agent with the        at least one oil.

In some embodiments, the methods of manufacturing the pharmaceuticalcompositions described herein further comprise:

-   -   Formulating the pharmaceutical composition a form suitable for        oral delivery.

It is within the knowledge of a skilled artisan that the order of mixingand the order of addition of the individual components can be modifiedto meet any specific needs.

In some embodiments, inert gas, such as, for example, N₂ or CO₂, may beused in the manufacturing process, to prevent oxidation of the at leastone oil (or one or more other components) during the manufacturingprocess. The manufacturing process may be conducted in a closed reactorhaving an internal impeller. In this reactor, N₂ and/or CO₂ may besupplied.

In some embodiments, a high shear mixer is used. In some embodiments,other means suitable for generating a homogenous formulation, as definedabove, from the nanoparticles and the at least one biopolymer is used.

In some embodiments, the method further comprises suspending the matrixcarrier composition in at least one oil until homogenous distribution,as defined above, of the solid phase is achieved using the airlift orboiling layer technologies. The oil used in preparing the suspension maybe the same as or different from the at least one oil used in preparingthe matrix carrier composition.

The airlift technology involves the insertion of gas bubbles into aliquid composition. The bubble flow efficiently mixes the liquids and/orsuspensions and may facilitate particle interaction and/or adsorption.Specifically, the bubble surface adsorbs the different particles andgenerates shock waves during bubble destruction. This gas “boilinglayer” forms flying micro-drops and/or particles in the arising flow ofthe gas above the liquid surface. Micro-drops may be created bysprinkler with or without an ultrasound transducer. The boiling layerimproves the interaction of the particles and the liquid (oil) drops dueto increased frequency and energy of collisions.

In some embodiments, the biopolymer may undergo dry milling/groundingbefore use. In some embodiments, decreasing the particle size of thebiopolymer (e.g., in order to improve homogeneity) to sizes of, forexample, less than 10 μm may be achieved by homogenization of thebiopolymer in the at least one oil prior to addition of thenanoparticles. In some embodiments, vacuum methods may be used to removemoisture and air from the biopolymer and/or lyophilized pharmaceuticalagent mix (in oil or without oil).

In some embodiments, in order to improve adsorption, the biopolymer andnanoparticles surface is released from air micro-bubbles and small waterdroplets. This may be achieved by vacuum drying and gas removal or/anddrying by passing of drying agent (such as, for example, gases like N₂,CO₂, He or other inert gases) through the mix. Gas removal may also beperformed by centrifugation or/and deep vacuum.

In some embodiments, the method of manufacturing a matrix carriercomposition further comprises the step of adding additional oilfollowing the addition of the at least one oil. The term “additionaloil” encompasses an oil or mixture of oils, as described elsewhereherein. In some embodiments, the additional oil, oil or mixture of oilshas a higher viscosity than the first-added oil or mixture of oils. Insome embodiments, without wishing to be bound by any theory or mechanismof action, the use of a higher viscosity oil or oil mixture at thisstage can enable formation of ordered structures in the composition.

In some embodiments, the method of manufacturing a matrix carriercomposition further comprises the step of adding a third oil or mixtureof oils after addition of the above-described at least one oil.

In some embodiments, the at least one oil comprises at least one wax. Insome embodiments, the at least one wax is heated. In some embodiments,the at least one wax is pulverized. In some embodiments, the at leastone wax is both heated and pulverized. In some embodiments, the heatingand/or pulverization are performed prior to blending with the othercomponents. In some embodiments, the at least one wax remains hot whileblending with the other components begins. In some embodiments, theheating and/or pulverization are performed during blending with theother components. In some embodiments, the heating and/or pulverizationare performed both prior to and during blending with the othercomponents.

In some embodiments, wax may further be used as an additionalstabilizing rheological component. Wax has no hydrophilic surface andhas internal energy which is lower than the internal energy ofpolysaccharides and silica. Low internal energy of wax is related to thelow melting point of wax. High melting point may deactivate/denaturatethe pharmaceutical agent during the manufacturing process of thecomposition. To this aim, eutectic mix with lower melting temperaturebetween may be prepared by premixing the wax with additional wax or oilhaving high thermal stability. Use of the eutectic mix of wax and oilwith the pharmaceutical agent mix, while mixing gently (for example, atabout 2000-2500 rpm), enables cooling of eutectic mix and thus a solidand a liquid disperse phases are formed. Such a process may furtherenable the formation of small solid wax droplets. Without wishing to bebound by any theory of mechanism of action, when such small solid fatdroplet are formed, then these droplets, after administration, will notbe digested by lipases and would go to feces, and hence the effectiveratio of the anti-cancer reagent penetration will be increasedrelatively to liquid composition without wax and the additional solidphase. The choice of type of wax with a desired predetermined meltingpoint and its final concentration as well as method of its insertion inthe formulation enables the to regulate the dispersion as well asstability and consistence of the final formulation.

The oil or mixture of oils used for each pharmaceutical agent may be thesame or different.

In some embodiments, two or more different pharmaceutical agents may becombined within a single mixture of nanoparticles associated with thebiopolymer and then mixed with the oil components.

In some embodiments two or more pharmaceutical agents may beindividually combined with the nanoparticles associated with thebiopolymer and then these individual mixtures may be further mixedtogether with the oil components.

In some embodiments, the step of mixing a pharmaceutical agent with atleast one oil comprises the step of directly dissolving thepharmaceutical agent into the at least one oil. In some embodiments, asolution of the pharmaceutical agent in a solvent, such as water, ismixed with the at least one oil and the solvent is then removed. In someembodiments a solution of the pharmaceutical agent may be lyophilizedpreviously to being added to oil.

In some embodiments, the pharmaceutical agent forms a suspension whenmixed with the at least one oil. In some embodiments, the pharmaceuticalagent is dissolved in the at least one oil.

In some embodiments, the pharmaceutical agent is mixed with the at leastone oil in the presence of an alcohol.

In some embodiments, the pharmaceutical agent is mixed with the at leastone oil in the presence of polyethylene glycol present. In someembodiments the polyethylene glycol has a molecular weight in the200-8000 dalton range.

In some embodiments the pharmaceutical agent is mixed with the at leastone oil in the presence of perfluorocarbon. In some embodiments theperfluorocarbon is a liquid at room temperature.

In some embodiments, the pharmaceutical agent is mixed with the at leastone oil under anhydrous conditions. In some embodiments, moisture ispresent. In some embodiments, an aqueous solution of the pharmaceuticalagent is mixed with the at least one oil.

In some embodiments the pharmaceutical agent may be dissolved in oil andstay there for 10-48 hours or more previously to formulationpreparation.

In some embodiments, a combination of several pharmaceutical agents maybe formulated into one formulation. In some embodiments, preparation ofparticulate matter comprising each pharmaceutical agent is doneseparately and at the last step, the separate particulate matters areput together without additional mixing. Several technologies may be usedto prevent comparative adsorption of the pharmaceutical agents on thesolid phase as well as chemical interaction between them: thepharmaceutical agents are each formulated in a jell (non liquidformulation) or with any bio-available solidifications; thepharmaceutical agent formulations may be prepared as a mix of smalldrops or particles from practically solid materials (at roomtemperature) and/or suspension in liquid lipid phase of solid orsemi-solid balls and/or pieces with pharmaceutical agents.

In some embodiments, the formulation method of pharmaceutical agentsincluding association of the pharmaceutical agents with the biopolymerand/or nanoparticle may be performed, for example, by the “Sandwich”technology (the “sandwich” technology provides a formation of multilayerstructure which consists of consequently adsorbed components. Thus, theprocess provides sequential spatial and temporal adsorption withpredetermined properties) Exposure may be performed for 30 min-72 hoursdepending on the pharmaceutical agent and the therapy needs (which mayeffect PK and PD). Further mixing with other ingredients may bepreformed, for example: for preliminary adsorption 0 to 100% ofnanoparticles or biopolymers may be used, according to required PK andPD. Adsorption activity of nanoparticles and/or biopolymers may beachieved by preliminary treatment in homogenizer and/or by ultra-sound.For some pharmaceutical agents, colloidal metals, such as, for example,Zn, Cu, Fe, and the like, may be used as structure forming element.Controlled electrolysis with further lyophilization or vacuum drying maybe used to implement the colloidal metals in the formulation.

Also provided are products of the manufacturing processes describedherein.

According to further embodiments, and as shown in Example 7, in order toextract the pharmaceutical agent from the matrix carrier compositioninto a solution, an extracting procedure should be used. The use of suchextraction procedures is indicative that the pharmaceutical agent isheld in the matrix carrier in a complex by non-covalent forces andtherefore the use of an organic solvent and surfactant are necessary inorder to extract said agent from the matrix.

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the following appended claims and claims hereafterintroduced be interpreted to include all such modifications,permutations, additions and sub-combinations as are within their truespirit and scope.

In the description and claims of the application, each of the words“comprise” “include” and “have”, and forms thereof, are not necessarilylimited to members in a list with which the words may be associated.

EXAMPLES

The following examples are intended to illustrate the disclosure andwithout however limiting the scope thereof.

Example 1 Matrix Carrier Pharmaceutical Composition Preparation—GeneralProtocol No. 1

The following process may be used to prepare pharmaceutical compositionsas described herein.

Step 1. Add pharmaceutical agent to at least one oil. Optionally, holdin refrigerator for 12-72 hours.

Step 2. Mix and/or homogenize biopolymer and silica into oils.

Step 3. Vacuum may be used for removing adsorbed gases.

Step 4. Continue mixing.

Step 5. Add enhancers, continue mixing.

Step 6. Packaging the formulation of step 5.

Example 2 Matrix Carrier Pharmaceutical Composition Preparation—GeneralProtocol No. 2

The following process may be used to prepare pharmaceutical compositionsas described herein.

Step 1. Optional dry milling of one or more biopolymers together(additional dry mixing).

Step 2: Insertion of part of the biopolymer mixture into an oil, mixing;insertion of part of silica, mixing and continue adding one afteranother until all of the silica and the biopolymers are incorporated.

Step 3. Vacuum with mixing for to remove gases.

Step 4. Addition of pharmaceutical agent, mixing.

Step 5. Optionally addition of enhancers, additional components, mixing.

Step 6. Packaging the formulation of step 5.

Example 3 Matrix Carrier Pharmaceutical Composition Preparation—GeneralProtocol No. 3

The following process may be used to prepare pharmaceutical compositionsas described herein.

Step 1. Inserting hydrophobic silica nanoparticles and polysaccharides(or mixture of the polysaccharides) into lipid or mix of lipids (oils)such as by using airlift with inert gases or boiling layer technologiesand mixing vigorously by shearing mixer or homogenizer until anhomogenous distributed oil based suspension is obtained.Step 2. Adding the pharmaceutical agent into the lipid/oil basedsuspension of step 1; it is important to control the temperature,intensity of mixing, and the oxidative properties of the gas phase ofthe reactor in which the mixing is performed.Step 3. Mixing the oil based suspension of step 2 until homogenousdistributed oil suspension is obtained.Step 4. Adding a targeting and/or enhancer component, such as, arginine;vitamins or co-enzymes to the homogenous distributed oil basedsuspension of step 3, and gently mixing with inert material agitatorunder inert atmosphere.Step 5. Adding while mixing, an additional oil, such as palm oil, and/orwax for physical stabilization of the formulation.Step 6. Packing the formulation of step 5.

Example 4 Matrix Carrier Pharmaceutical Composition Preparation—GeneralProtocol No. 4

The following process may be used to prepare pharmaceutical compositionsas described herein.

Step 1. Dry mixing the hydrophobic silica nanoparticles andpolysaccharides or mix of the polysaccharides in a reactor with liquidor gas dynamic sealing (sealing with controlled leakage of the workingmedium provides protection of the bearing, valves and surroundings fromcontamination by aerosol and nanoparticles). Dry mixing may be performedby an agitator with protected blades, or by gas using a boiling layertechnology.Step 2. Inserting a pharmaceutical agent into lipids, oil or mix ofoils.Step 3. Mixing gently the lipid based suspension of steps 2 and thepowder of silica nanoparticles and polysaccharide of step 1, untilhomogenous distribution of the solid phase is achieved.Step 4. Adding a targeting and/or enhancer component, such as, arginine;vitamins or co-enzymes to the homogenous distributed oil basedsuspension of step 3, and gently mixing with inert material agitatorunder inert atmosphere.Step 5. Adding while mixing, an additional oil, such as palm oil, and/orwax for physical stabilization of the formulation.Step 6. Packing the formulation of step 5.

Example 5 Matrix Carrier Pharmaceutical Composition Preparation—GeneralProtocol No. 5

The following process may be used to prepare pharmaceutical compositionsas described herein.

-   -   1. Activation of the second solid phase surface of the        matrix-carrier by additional milling, vacuum treatment, chemical        or ultra-sound cleaning or reduction.    -   2. Mixing activated biopolymers (such as polysaccharides) with        liquid oils under vacuum or in inert atmosphere.    -   3. Inserting nanoparticles into oils and additional vacuum        treatment for removing air from particles surface    -   4. Inserting pharmaceutical agent(s) into pure oils, oils with        hydrophobic nanoparticles or oils with biopolymers with or        without silica, depending on the hydrophobicity of the        pharmaceutical agent.    -   5. Mixing and homogenization of the system takes into account        sensitivity of the pharmaceutical agents to mechanical stress.        This process is provided under inert atmosphere with control of        temperature, rate and time treatment.    -   6. The homogenization allows inserting into the material        additional energy which may decreases viscosity of the materials        and promote its packing.    -   7. The maturation of the material may be achieved by maintaining        under controlled temperature (in the range of 1-25° C.), for        1-72 hours. The maturation may increase viscosity and energy of        binding matrix-carrier with the pharmaceutical agent.

Example 6 Analysis and Comparison of Insulin within or without theMatrix Carrier

LC/MS stability analysis of insulin samples was performed in order toevaluate insulin stability within or without the Matrix CarrierFormulation at different time points (0, 2 weeks, 1 month and 3 months)during storage at 4-5° C. Insulin Bulk row material without the MatrixCarrier Formulation was stored in glass vials. Insulin within the MatrixCarrier Formulation, which composition is detailed in the Example 7, wascapsulated into gelatin capsules (Capsugel, size 00). In order toperform HPLC and LC/MS analysis, the samples followed similar extractionprocedure as detailed in Example 7 below.

FIG. 1, panel A demonstrate the LC/MS of raw bulk insulin (that is,insulin not within the matrix carrier) after 3 month of storage at 4-5°.FIG. 1, panel B demonstrate the LC/MS of insulin extracted from MatrixCarrier Formulation, after 3 month of storage at 4-5°.

Comparison of the LC/MS spectrums of FIG. 1 panels A and B show that thetwo spectrums are similar. The results suggest that the Matrix CarrierFormulation does not reduce the stability of the pharmaceutical agentand that the bonds between the pharmaceutical agent (Insulin) and theMatrix Carrier are not covalent.

Example 7 Extraction of Pharmaceutical Agent from the Matrix Carrier

In order to demonstrate that the pharmaceutical agent is forming acomplex with the matrix carrier, while protecting it from the externalenvironment, two oral formulations with sensitive pharmaceutical agentsuch as proteins were tested. The tested pharmaceutical agents wereDNase and Insulin.

Composition of the DNase Formulation: (Packed in a Capsule)

50 g DNase 25 g Silica 80 g Jojoba oil 80 g Oblepicha oil 60 g Olive oil90 g Palm oil 75 g Amylopectin 25 g Beta-cyclodextrinComposition of the Insulin Formulation (Packed in a Capsule):

 2 g Insulin  30 g Silica R972  50 g Beta-cyclodextrin 200 g Nutriose 50 g Maltsorb 260 g Olive oil 260 g Palm oil 200 g Oblepicha oilMethods:

Each capsule of the DNase Formulation was treated in 20 ml water at 35°C., for −1 hour. The first sample was taken. 5 ml Hexane were added, andthe mixture was mixed gently, and then centrifuged at 3000 RPM for 10min. a second sample was taken. Then the mixture was mixed vigorouslyand centrifuged, and a third sample was taken. (and diluted by 5 folds).The DNase content was calculated from the peak area of DNase in thechromatogram against the calibration curve. The results are summarizedin the table below.

TABLE 1 DNAse amount per capsule as calculated by HPLC method CalculatedDNase weight (mg) DNase peak area 3rd 2nd 1st 3rd 2nd 1st 97.91 17.8612.67 21460.3 19570.7 13890.1 capsule 1 106.15 21.70 9.83 23265.423781.7 10767.7 capsule 2 101.61 19.64 11.64 22269.8 21522.2 12752.8capsule 3 97.59 16.69 8.34 21389.1 18293.5 9134.4 capsule 4 102.38 18.5910.97 22439.1 20371.1 12025.6 capsule 5 98.80 16.04 14.78 21653.817578.6 16194.6 capsule 6 127.23 22.44 11.68 27886.5 24594.40 12797.7capsule 7 101.94 18.42 11.06 22343.3 20183.10 12122.1 capsule 8 103.0420.51 10.75 22584.8 22471.90 11783.9 capsule 9 119.38 21.98 13.6526165.80 24084.00 14955.4 capsule 10 105.60 19.39 11.54 Av. 9.85 2.241.84 SD 9.33 11.55 15.99 RSDFurther analysis shows that addition of 2.5% of surfactant (such asTWEEN 20), result in additional 8-10% increase in recovery of the DNasefrom the matrix carrier composition. Similar results were repeated forInsulin as a pharmaceutical agent in the matrix carrier compositionformulation.

Furthermore, the Insulin formulation was tested by incubation withintestinal enzymes mix at 37° C. for various time lengths up to 16hours. The results show no degradation of Insulin.

Additional experiments were performed for dissolution of the Insulinformulation by incubation at 37° C. in different mediums such as: purewater, saline, acidic solution with pepsine, fetal porcine serum andsaline with 2.5% TWEEN 20. The matrix carrier decomposition was mainlyobserved in mediums that contain synthetic or natural blood surfactantssuch as, for example, Tween 20 or serum.

Example 8 Injection of Matrix Carrier Composition Comprising Insulin asCompared to Standard Insulin Injection

The following Insulin formulations were used:

Formulation I—Standard Insulin Formulation

-   -   Injection of insulin in PBS, 50 IU—Human recombinant Insulin in        lyophilized form was dissolved in phosphate buffer at a        concentration 50 IU/ml.        Formulation II—Matrix Carrier Composition

The matrix carrier composition with Insulin formulation, 50 IU—Thecomposition for the formulation is detailed in Example 7, above.

Experimental Details

The study included 8 animals (rats) in each group.

Blood samples were withdrawn under halothan anesthesia from the rattail. Blood glucose levels were measured from each blood samples byFreeStyle glucose meter, Abbott. After withdrawn, blood samples werekept in ice and then centrifuged at 3500 rpm, 4 C for plasma separation.Insulin level in rat plasma was measured by Human Insulin ELISA kit(Millipore kit (Cat. # EZHI-14K).

After the withdrawal of the first blood sample, rats were injected withFormulation I (insulin alone, 50 IU) or Formulation II (same Insulinwithin the matrix carrier composition, 50 IU). Additional blood sampleswere taken at time intervals after the injection: 3 hours, 6 hours, 9hours, 12 hours and 24 hours.

The results, illustrated in FIG. 2A show that blood glucose levels werereduced after injection of Formulation II, as compared to the standardinsulin injection (Formulation I). In addition, the results illustratedin FIG. 2B show that plasma concentration of the injected human insulinin the rats (measured by Human Insulin ELISA Millipore kit (Cat. #EZHI-14K), is still high after 25 hours if the rats were injected withFormulation II, as compared to the standard insulin formulationinjection (Formulation I).

The invention claimed is:
 1. A matrix carrier composition for use in apharmaceutical delivery system, the composition being a suspension of aparticulate matter in a continuous oil phase, the particulate mattercomprising an intermolecular association of at least: a first solidphase comprising nanoparticles having a hydrophobic surface, wherein thesize of the nanoparticles is in the range of about 5-1000 nm; a secondsolid phase, comprising a biopolymer having hydrophilic and hydrophobicparts; and the continuous phase being associated with said first andsaid second solid phases, wherein the weight of the biopolymer is atleast twice that of the nanoparticles.
 2. The matrix carrier compositionof claim 1, wherein the matrix carrier composition does not include asurfactant.
 3. The matrix carrier composition of claim 1, wherein thedensity of the first solid phase is higher than 1.4 g/cm³.
 4. The matrixcarrier composition of claim 1, wherein the nanoparticles have a surfacemodified to be hydrophobic.
 5. The matrix carrier composition of claim1, wherein the nanoparticles are selected from the group consisting ofsilica nanoparticles, fumed silica nanoparticles, zinc oxidenanoparticles, carbon nanoparticles, titanium oxide nanoparticles andcombinations thereof.
 6. The matrix carrier composition of claim 1,wherein the biopolymer has a structure selected from linear, cyclic andbranched biopolymer.
 7. The matrix carrier composition of claim 1,wherein the biopolymer comprises a biopolymer selected from a saccharideand a polysaccharide.
 8. The matrix carrier composition of claim 7,wherein the polysaccharide is selected from the group consisting of:starch, dextrin, cellulose, chitin, alpha glucan, beta glucan,amylopectin, glycogen, chitosan, cyclodextrin, mucopolysaccharide, andderivatives and combinations thereof.
 9. The matrix carrier compositionof claim 1, wherein the biopolymer comprises a structural proteinselected from the group consisting of: a high molecular weightstructural protein, a fibrous protein, a scleroprotein and combinationsthereof.
 10. The matrix carrier composition of claim 1, wherein the oilcomprises an oil or a combination of oils selected from the groupconsisting of: naturally-occurring oils, synthetic oils, waxes andcombinations thereof.
 11. The matrix carrier composition of claim 1,wherein the oil comprises an oil or a combination of oils selected froma group consisting of: sesame oil, olive oil, linseed oil, eveningprimrose oil, silicone oil, sea buckthorn oil, palm oil, andcombinations thereof; sunflower oil, corn oil, soybean oil, jojoba oil,marrow oil, grapeseed oil, hazelnut oil, apricot oil, macadamia oil,palm oil, almond oil, castor oil, and combinations thereof; oblepichaoil, jojoba oil, olive oil and combinations thereof; olive oil, linseedoil, oblepicha oil, sesame oil, palm oil and combinations thereof;jojoba oil, oblepicha oil, sesame oil, olive oil and combinationsthereof; wax, jojoba oil, oblepicha oil, sesame oil, olive oil andcombinations thereof; and linseed oil, oblepicha oil, olive oil, palmoil and combinations thereof.
 12. The matrix carrier composition ofclaim 1, wherein the oil comprises lanolin, a fatty alcohol, a fattyacid ester or a phenylsilicone.
 13. The matrix carrier composition ofclaim 1, further comprising an amino acid selected from the groupconsisting of: arginine, lysine, glutamic acid, aspartic acid andhistidine and combinations and derivatives thereof.
 14. The matrixcarrier composition of claim 1, wherein said composition furthercomprises at least one agent selected from the group consisting of: anactive pharmaceutical agent, nutritional agent, a targeting agent, anenhancer, an anti-oxidant, and combinations thereof.
 15. The matrixcarrier composition of claim 1, configured for topical administration.16. The matrix carrier composition of claim 1, configured for parenteraladministration.
 17. A method of manufacturing the matrix carriercomposition of claim 1, the method comprising: a. mixing a first solidphase with an oil, wherein the first solid phase comprises nanoparticleshaving a hydrophobic surface and particle size of about 5-1000 nm; b.activating a second solid phase, wherein the second solid phasecomprises a biopolymer having hydrophilic and hydrophobic parts andwherein the weight of the biopolymer is at least twice that of thenanoparticles; and c. adding the activated second solid phase into anoil; and d. mixing the oil comprising the first solid phase and the oilcomprising the activated second solid phase.
 18. The method of claim 17,wherein activating comprises milling, vacuum treatment, chemicaltreatment, ultrasonic treatment or any combination thereof.
 19. Themethod of claim 17, further comprising adding an agent selected from thegroup consisting of: a pharmaceutical agent, a nutritional agent, atargeting agent, an enhancer, an amino acid and combinations thereofoptionally pre-mixed with an oil, into a) the oil comprising theactivated second solid phase; b) the oil comprising the first solidphase; or c) a mixture of the oil comprising the activated second solidphase and the oil comprising the first solid phase.